The topic of pharmacogenetics and pharmacokinetics will be explored in this presentation, with a focus on how the way drugs are metabolized can be affected by genetics, and how this information can be used to personalize drug therapy. Topics such as drug response, drug metabolism, drug-drug interactions, and adverse drug reactions will be covered. The importance of pharmacokinetic profiling and therapeutic drug monitoring in ensuring drug safety and effectiveness will also be discussed. Valuable insights into the field of pharmacology and its potential to revolutionize patient care will be provided, making this presentation of interest to healthcare professionals, researchers, and those who wish to learn more about personalized medicine. The world of pharmacogenomics and genomic medicine will be delved into.
The presentation will also highlight the importance of pharmacodynamics and pharmacokinetics in drug development and clinical pharmacology.
By the end of this presentation, you will have a better understanding of the underlying principles of pharmacogenetics and pharmacokinetics and how they can be applied to optimize drug therapy for individual patients. This knowledge is essential for anyone involved in healthcare and drug development, as it has the potential to improve treatment outcomes and reduce adverse drug reactions.
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
Nomograms and tabulations in design of dosage regimens pavithra vinayak
Nomograms and tabulations in the design of dosage regimens --- NOMOGRAM IN UREMIC PATIENTS: NOMOGRAM FOR RELATIONSHIP BETWEEN CREATININE CLEARANCE AND ELIMINATION RATE CONSTANT FOR FOUR DRUGS clinical pharmacokinetics and therapeutic drug monitoring ---fifth PharmD notes
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
Nomograms and tabulations in design of dosage regimens pavithra vinayak
Nomograms and tabulations in the design of dosage regimens --- NOMOGRAM IN UREMIC PATIENTS: NOMOGRAM FOR RELATIONSHIP BETWEEN CREATININE CLEARANCE AND ELIMINATION RATE CONSTANT FOR FOUR DRUGS clinical pharmacokinetics and therapeutic drug monitoring ---fifth PharmD notes
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
adaptive methods are doing with feedback in population pharmacokinetics---- clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Individualisation and optimization of drug dosing regimenJyoti Nautiyal
Drug dosing regimen, dosing frequency, individualisation, Steps Involved in Individualization of Dosage Regimen, optimization, variability, Clinical experience with individualization and optimization based on plasma drug levels.
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
adaptive methods are doing with feedback in population pharmacokinetics---- clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Individualisation and optimization of drug dosing regimenJyoti Nautiyal
Drug dosing regimen, dosing frequency, individualisation, Steps Involved in Individualization of Dosage Regimen, optimization, variability, Clinical experience with individualization and optimization based on plasma drug levels.
pharmacogenomics helps to improve healthcare sector by providing information about variability among genes for a particular class of drug hence reduces adverse drug reactions.
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”)
DNA sequence variations are sometimes described as mutations and sometimes as polymorphisms. A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population.
Polymorphic sequence variants usually do not cause overt debilitating diseases. Many are found outside of genes and are completely neutral in effect. Others may be found within genes, but may influence characteristics such as height and hair colour rather than characteristics of medical importance.
However, polymorphic sequence variation does contribute to disease susceptibility and can also influence drug responses (Single Nucleotide Polymorphisms).
It promotes diversity and persists over many generations because no single form has an overall advantage or disadvantage over the others in terms of natural selection.
It is originally used to describe visible forms of genes, but now used to include cryptic modes such as blood types, which require a blood test to decode.
In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to generally be considered polymorphic.
Gene polymorphisms can occur in any region of the genome.
The majority of polymorphisms are silent, meaning they do not alter the function or expression of a gene.
Some polymorphism is visible. For example, in dogs the E locus, can have any of five different alleles, known as E, Em, Eg, Eh, and e. Varying combinations of these alleles contribute to the pigmentation and patterns seen in dog coats.
Human blood groups is also a polymorphic effect.
Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene.
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.
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.
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.
pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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
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
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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
- 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
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
2. • Inter-individual variability in drug response be it efficacy or safety, is common and likely
to become an increasing problem globally.
• Reasons for this inter-individual variability include genomic factors, an area of study
called Pharmacogenomics.
VED PATEL 2
• Pharmacogenetics involves the search for genetic
variations that lead to interindividual differences in
drug response.
• The term pharmacogenetics often is used
interchangeably with the term pharmacogenomics.
• However, pharmacogenetics generally refers to
monogenetic variants that affect drug response,
whereas pharmacogenomics refers to the entire
spectrum of genes that interact to determine drug
efficacy and safety.
3. • The goals of pharmacogenetics are to optimize drug therapy and limit drug toxicity
based on an individual's genetic profile.
• Thus, pharmacogenetics aims to use genetic information to choose a drug,
drug dose, and
treatment duration
• That will have the greatest likelihood for achieving therapeutic outcomes with the least
potential for harm in a given patient.
• Genotype-guided therapy is already a reality for some diseases, such as cancer and
cystic fibrosis, where novel drugs have been developed to target specific mutations.
EXAMPLES-Trastuzumab (HER2)
Dasatanib (BCR-ABL)
Sunitinib (CSFIR + more)
3
Application of genotype-guided cancer therapy in solid tumours, JAI N Patel, Pharmacogenomics 2014 15:1, 79-93
4. HISTORY
VED PATEL 4
2000- Pharmacogenetics Research Network & Pharm GKB (database)
1977-1988 – Increasing number of genetic varients and their corrensponding
enzymatic functions were reported.
Werner kalow, German clinical pharmacologist created framework for
pharmacogenetics in his book pharmacogenetics: heredity and drug
response.
1959- Friedrich vogel, German genecist coined term ‘Pharmacogenetics’
1957- Arno Motulsky, a pioneer of medical genetics, published paper titled,
“Drug reactions, Enzymes, and Biochemical Genetics.”
1950- Reports of primaquine – caused hemolysis in individual who were
G6PD deficient.
5. Basics of genetics
VED PATEL 5
• The human genome contains more than 3 billion nucleotide base pairs, which code for
approximately 20,000 protein-coding genes.
• Two purine nucleotide bases,
adenine (A) and guanine (G),
• Two pyrimidine nucleotide bases,
cytosine (C) and thymidine (T),
• With purines and pyrimidines always pairing together as A-T and C-G in the two
strands that make up the DNA double-helix.
• Most nucleotide base pairs are identical from person to person, with only 0.1%
contributing to individual differences.
6. Basics of genetics
VED PATEL 6
• According to the central dogma when one strand of DNA is transcribed into RNA and
translated to make proteins, three consecutive nucleotides form a codon.
• Each codon specifies an amino acid or amino acid chain termination.
• For example, the nucleotide sequence, or codon, GGA specifies the amino acid
glycine.
• The genetic code has substantial redundancy, in that two or more codons code for the
same amino acid. For example, GGC, GGG, and GGT also code for glycine.
• Amino acids are the basic constituents of proteins, which mediate all cellular functions.
Only 20 different amino acids, in various arrangements, form the basic units of all the
proteins in the human body.
7. Basics of genetics
VED PATEL 7
• A gene is a series of codons that specifies a particular protein.
• Genes contain several regions: Exons that encode for the final protein,
Introns that consist of intervening noncoding regions
Regulatory regions that control gene transcription
• In most cases, an individual carries two alleles, one from each parent, at each gene
locus.
• An allele is defined as the sequence of nucleic acid bases at a given gene chromosomal
locus.
• Two identical alleles make up a homozygous genotype, and two different alleles make
up a heterozygous genotype.
• A phenotype refers to the outward expression of the genotype.
9. Type of genetic variations
VED PATEL 9
• Genetic variations occur as either rare defects or polymorphisms.
• Polymorphisms are defined as variations in the genome that occur at a frequency of at
least 1% in the human population.
• For example, the genes encoding the CYP enzymes 2A6 2C9, 2C19, 2D6, and 3A4 are
polymorphic, with functional gene variants of greater than 1% occurring in different
racial groups.
• In contrast, rare mutations occur in less than 1% of the population and cause inherited
diseases such as cystic fibrosis, hemophilia, and Huntington's disease.
• Common diseases, such as essential hypertension and diabetes mellitus, are polygenic
in that multiple genetic polymorphisms in conjunction with environmental factors
contribute to the disease susceptibility.
10. VED PATEL 10
• Single-nucleotide polymorphisms abbreviated as SNPs and pronounced "snips," are the
most common genetic variations in human DNA, occurring once approximately every
300 base pairs.
• More than 20 million SNPs have been mapped thus far in the human genome.
• SNPs occur when one nucleotide base pair replaces another.
• Thus, SNPs are single-base differences that exist between individuals.
• Nucleotide substitution results in two possible alleles. One allele, typically either the most
commonly occurring allele or the allele originally sequenced, is considered the wild type,
and the alternative allele is considered the variant allele.
• SNPs such as this that result in amino acid substitution are referred to as
nonsynonymous. SNPs that do not result in amino acid substitution are called
synonymous, which in many cases are silent.
11. 11
Martínez, M.F., Quiñones, L.A. (2018). Relationship Between Pharmacokinetics and Pharmacogenomics and Its Impact on Drug
Choice and Dose Regimens. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer
12. VED PATEL 12
Nucleotide sequence of the β2-adrenergic receptor gene from codons 13 through 19.
(A) Nucleotide sequence of the wild-type allele with adenine (A) at nucleotide position 46 (underlined) located in codon
16 of the β2-adrenergic receptor gene. Arginine (Arg), with an average. The AGA codon designates the amino acid
frequency of 39% in the human population. (B) Nucleotide sequence of the variant allele with guanine (G) at
nucleotide position 46 (underlined), located in codon 16. The GGA codon designates the amino acid glycine (Gly),
which occurs at an average frequency of 61%.
• Alterations in receptor downregulation on prolonged exposure to β2-receptor agonists.
13. Other types of genetic variations
VED PATEL 13
• Insertion-deletion polymorphisms, in which a nucleotide or nucleotide sequence is
either added to or deleted from a DNA sequence.
• Tandem repeats, in which a nucleotide sequence repeats in tandem (eg, if "AG" is
the nucleotide repeat unit, "AGAGAGAGAG" is a five-tandem repeat).
• Frameshift mutation, in which there is an insertion/deletion polymorphism, and the
number of nucleotides added or lost is not a multiple of 3, resulting in of the gene's
reading frame.
• Defective splicing, in which an internal polypeptide segment is abnormally
removed, and the ends of the remaining polypeptide chain are joined.
• Aberrant splice site, in which processing of the protein occurs at an alternate site.
• Premature stop codon polymorphisms, in which there is premature termination of
the polypeptide chain by a stop codon.
• Copy number variants, in which entire copies of genes or gene segments more than
1 kb in size are duplicated, deleted, or rearranged.
14. Polymorphism in genes of drug metabolic enzymes.
VED PATEL 14
• Polymorphisms in the drug-metabolizing enzymes represent the first recognized
and, so far, the most documented examples of genetic variants with consequences in
drug response and toxicity.
• There are 70 drugs that include pharmacogenetic information related to
polymorphisms in drug-metabolizing enzymes that contribute to variable drug
response.
• Currently, 57 different CYP isoenzymes have been documented to be present In
humans, with 42 involved in the metabolism of exogenous xenobiotics and
endogenous substances such as steroids and prostaglandins.
• Fifteen of these isoenzymes are known to be involved in the metabolism of drugs,
but significant interindividual variabilities in enzyme activity exist as a result of
induction, inhibition, and genetic inheritance.
15. 15
• Functional genetic polymorphism has been discovered for CYP2A6, CYP2B6,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
Martínez, M.F., Quiñones, L.A. (2018). Relationship Between Pharmacokinetics and Pharmacogenomics and Its Impact on Drug
Choice and Dose Regimens. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer
16. Single gene PK disorders
VED PATEL 16
Pseudocholinesterase
deficiency
Pseudocholinesterase is a plasma enzyme produced in the liver that is
responsible for the metabolism of common muscle relaxants, including
succinylcholine and mivacurium.
• side effect of certain medications
• prolonged muscular paralysis
Acute intermittent
porphyria
Acute intermittent porphyria (AIP) is a pharmacogenetic disease caused
by a porphyrin metabolic defect characterized by a lack of
porphobilinogen deaminase and a rise in the activity of delta-
aminolevulinic acid synthase—two essential enzymes required for heme
production.
• stomach discomfort, vomiting, muscular weakness, constipation, and
neuropsychiatric symptoms during an episode.
• Clinical episodes are produced by many drugs (including barbiturates,
antiseizure drugs, and sulfonamide antibiotics)
17. VED PATEL 17
Drug acetylation
deficiency
• Two genes (NAT 1) and (NAT 2) are now known to control N-acetyl
transferase (NAT), with NAT 2 A and B accounting for clinically
significant metabolic variance
• Caffeine, isoniazid, nitrazepam, and sulfonamides are among the
many common medications that are acetylated.
19. CYP2D6
VED PATEL 19
• It is responsible for the metabolism Of as much as 25% Of commonly prescribed
drugs
• Polymorphisms in the CYP2D6 gene are the best characterized among all of the
CYP variants.
• It is estimated that approximately 10% of the Caucasian population, 1% of the
Asian population, and between 0% and 19% of the African population have a PM
phenotype of CYP2D6 (McGraw and Waller, 2012), resulting in increased plasma
concentration of the parent drug due to decreased metabolic clearance.
20. 20
Y. W. Francis Lam,, Chapter 1 - Principles of Pharmacogenomics: Pharmacokinetic, Pharmacodynamic, and Clinical Implications, Pharmacogenomics
(Second Edition), Academic Press, 2019, Pages 1-53, ISBN 9780128126264
VED PATEL
23. CY1A2
VED PATEL 23
• CYP1A2 activity varies widely with genetic polymorphisms contributing to
observed differences in levels of gene expression.
• CYP1A2 is responsible for the metabolism of about 5% of marketed drugs
including fluvoxamine, clozapine, olanzapine, and theophylline.
• Approximately 15% of the Japanese, 5% of the Chinese, and 5% of the Australian
populations are classified as CYPIA2 poor metabolizers.
• The most frequent allelic variant is CYPIA2*1F, which results in an increased
expression caused by an SNP in the upstream promoter region.
• Enhanced enzyme levels are thought to cause faster substrate clearance, which has
been associated with treatment failures for clozapine in smokers with the *IF allele
(Eap et al, 2004).
• CYPIA2*1C is also an SNP in the upstream promoter region that results in
decreased enzyme expression and has a prevalence up to 25% in Asian populations
(McGraw and Waller, 2012).
24. CYP2C9
VED PATEL 24
• CYP2C9 has at least 30 different allelic variants with the two most common
being CYP2C9*2 and *3.
• Both of these variants result in reduced CYP2C9 activity and are carried by
about 35% of the Caucasian population.
• CYP2C9 is a major contributor to the metabolism of the narrow therapeutic
index blood thinner warfarin.
• When a patient has one of these two polymorphisms, the dose of warfarin
needed for clinically relevant anticoagulation is generally much less since drug
clearance is reduced.
26. CYP2C19
VED PATEL 26
• CYP2C19 is a highly polymorphic drug-metabolizing enzyme with at least 30
variants reported
• Polymorphisms in CYP2C19 result in variable drug response to clopidogrel and
several antidepressants.
• The PM phenotype is often the result of two null alleles, CYP2C19*2, and *3.
• Both alleles produce truncated, non-functional CYP2C19 through the
introduction of a stop codon.
• The allelic frequency of CYP2C19*2 has been shown to be 15% in Africans,
29%—35% in Asians, 12%—15% in Caucasians, and 61% in Oceanians.
• CYP2C19*3 is mainly found in Asians (596—9%) with very low frequency in
Caucasians (0.5%)
27. VED PATEL 27
EX-
• IMs and PMs of CYP2C19 may have reduced response to the antiplatelet agent
clopidogrel. This is because clopidogrel is a prodrug that requires conversion via
CYP2C19 to its active form, as shown in In IMs and PMs, clopidogrel may be less
effective at inhibiting platelet aggregation and preventing cardiovascular events
than in EMs.
• Patients that have this UM phenotype are either heterozygous or homozygous for
CYP2C19*17.
• Carriers of this allele are associated with higher risk for bleeding due to the
increased metabolism of clopidogrel to the active metabolite (Sibbing et ai, 2010).
28. CYP3A4
VED PATEL 28
• CYP3A4 is the most abundant CYP450 in the liver and metabolizes over 50% of
the clinically used drugs.
• In addition, the liver expression of CYP3A4 is variable between individuals.
• To date, over 20 allelic variants of CYP3A4 have been identified.
• Despite the large number of variants, there is limited data demonstrating any
clinical significance for CYP3A4 substrates.
• The CYP3A4*2 allele has a non-synonymous SNP that is found in about 2.7% of
the Caucasian population and has some decreased clearance for the calcium
channel blocker nifedipine