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.
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
Bayesian theory in population pharmacokinetics--
1) INTRODUCTION TO BAYESIAN THEORY
2)BAYESIAN PROBABILITY TO DOSING OF DRUGS
3)APPLICATIONS AND USES OF BAYESIAN THEORY IN APPLIED PHARMACOKINETICS:
therapeutic drug monitoring and clinical pharmacokinetics-fifth pharm d notes
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
Bayesian theory in population pharmacokinetics--
1) INTRODUCTION TO BAYESIAN THEORY
2)BAYESIAN PROBABILITY TO DOSING OF DRUGS
3)APPLICATIONS AND USES OF BAYESIAN THEORY IN APPLIED PHARMACOKINETICS:
therapeutic drug monitoring and clinical pharmacokinetics-fifth pharm d notes
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.
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
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
pharmacogenomics helps to improve healthcare sector by providing information about variability among genes for a particular class of drug hence reduces adverse drug reactions.
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.
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
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
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”)
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
Pharmacogenetics d and effect on determination of drug dosing in PharmacotherapyChiranjibBagchi1
Pharmacogenomics is a n upcoming issue in medicine and health which might be recognised as a future medicine.People might resort into genetic testing before being prescribed by a drug to optimise it,s efficacy and prevent toxicity.
Hence it definitely will have a personal, economical, societal, legal and ethical connotation and will not be restricted to merely a scientific and individual health related issue .So whole of the scientific fraternity and the medical and allied healthcareprofessional, legal system and political decision makers , drug manufacturers all should be held immensely responsible for future decision making to make decisions or creating guidelines and regulations to solicit the problems arising out of the application of new scientific discoveries based on Pharmacogenomics in future. Thus pharmacogenomics might come into a rescue for a particular group of persons benefitting out of the genetic testing in terms of successful drug therapy but others might deny testing for being marked to be a treatment orphan in the light of insurance providers. A mystereous and challenging situation might be awating for whigh the world human societyand community at large should get themselves prepared for.
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 is a set of powerpoint slides with self-assessment questions interspersed throuought on drug metabolism and pharmacogenetics. The aim is to understand the mechanism of clinically significant drug interactions, recognize potentially clinically significant genetic influences on drug efficacy and toxicity, and genetic predispositions to disease due to altered drug metabolism or transport. This resource is appropriate for medical students or graduate healthcare professionals such as nursing students.
REVIEW OF LITERATURE AND SOURCES OF INFORMATIONAmeena Kadar
Different types of reviews of literature and it's sources are included in this PowerPoint. A review of the literature is an inevitable part of the research process.
Anemia is one of the most commonly seen condition predominantly in women due to various causes such as some chronic infection conditions and all. There are different types of anemias are there here we discuss mainly about Iron deficiency and sickle cell anemia.
Antibiotic Stewardship by Anushri Srivastava.pptxAnushriSrivastav
Stewardship is the act of taking good care of something.
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
WHO launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS) in 2015 to fill knowledge gaps and inform strategies at all levels.
ACCORDING TO apic.org,
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
ACCORDING TO pewtrusts.org,
Antibiotic stewardship refers to efforts in doctors’ offices, hospitals, long term care facilities, and other health care settings to ensure that antibiotics are used only when necessary and appropriate
According to WHO,
Antimicrobial stewardship is a systematic approach to educate and support health care professionals to follow evidence-based guidelines for prescribing and administering antimicrobials
In 1996, John McGowan and Dale Gerding first applied the term antimicrobial stewardship, where they suggested a causal association between antimicrobial agent use and resistance. They also focused on the urgency of large-scale controlled trials of antimicrobial-use regulation employing sophisticated epidemiologic methods, molecular typing, and precise resistance mechanism analysis.
Antimicrobial Stewardship(AMS) refers to the optimal selection, dosing, and duration of antimicrobial treatment resulting in the best clinical outcome with minimal side effects to the patients and minimal impact on subsequent resistance.
According to the 2019 report, in the US, more than 2.8 million antibiotic-resistant infections occur each year, and more than 35000 people die. In addition to this, it also mentioned that 223,900 cases of Clostridoides difficile occurred in 2017, of which 12800 people died. The report did not include viruses or parasites
VISION
Being proactive
Supporting optimal animal and human health
Exploring ways to reduce overall use of antimicrobials
Using the drugs that prevent and treat disease by killing microscopic organisms in a responsible way
GOAL
to prevent the generation and spread of antimicrobial resistance (AMR). Doing so will preserve the effectiveness of these drugs in animals and humans for years to come.
being to preserve human and animal health and the effectiveness of antimicrobial medications.
to implement a multidisciplinary approach in assembling a stewardship team to include an infectious disease physician, a clinical pharmacist with infectious diseases training, infection preventionist, and a close collaboration with the staff in the clinical microbiology laboratory
to prevent antimicrobial overuse, misuse and abuse.
to minimize the developme
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Alongside the 77th World Health Assembly in Geneva on 28 May 2024, we launched the second version of our Index, allowing us to track progress and give new insights into what needs to be done to keep populations healthier for longer.
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Professor Orazio Schillaci, Minister of Health, Italy
Dr Hans Groth, Chairman of the Board, World Demographic & Ageing Forum
Professor Ilona Kickbusch, Founder and Chair, Global Health Centre, Geneva Graduate Institute and co-chair, World Health Summit Council
Dr Natasha Azzopardi Muscat, Director, Country Health Policies and Systems Division, World Health Organisation EURO
Dr Marta Lomazzi, Executive Manager, World Federation of Public Health Associations
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1. GENETIC POLYMORPHISM IN DRUG
METABOLISM
AMEENA KADAR K A
SECOND SEM M PHARM
DEPT. OF PHARMACY PRACTICE
SANJO COLLEGE OF PHARMACEUTICAL STUDIES
2. PHARMACOGNETICS
The term "pharmacogenetics" was first coined by Friedrich Vogel in
1959, who defined it as the "study of the role of genetics in drug response."
It is one of the most rapidly growing areas and is becoming increasingly
important in clinical pharmacy.
The pharmacogenetics of drug-metabolizing enzymes is a prominent focus
of this field, because genetic makeup is responsible for a significant portion
of drug-induced toxicity; many drugs are metabolized by enzymes that are
encoded by polymorphically expressed genes.
2
3. 3
Pharmacogenetics is the study of the genetic basis of individual patient
variability in the response to drug therapy.
It has been defined as the study of variability in drug response due to heredity
Pharmacogenetics allows for individualization of drug therapy.
Pharmacogenomics is closely related to pharmacogenetics and is considered
to be an equivalent or overlapping field.
Pharmacogenomics involves study of the role of genes and their genetic
variations (DNA, RNA level) in the molecular basis of disease and the resulting
pharmacologic impact of drugs on that disease.
4. 4
Pharmacogenetic = pharma + genetic
Pharma - the Greek word ie ; pharmacon related to drugs
Genetic - related to genes or genomes.
Pharmacogenetic studies have also allowed us to better understand the
pharmacology of medications used to treat neurologic & psychiatric
disorders.
Pharmacogenetic focuses on the influence of single genes on drug response.
Ultimately, the goal of pharmacogenetics is to predict a patient’s genetic
response to a specific drug as a means of delivering the best possible
medical treatment.
By predicting the drug response of an individual, it will be possible to
increase the success of therapies and reduce the incidence of adverse side
effects.
5. APPLICATIONS OF PHARMACOGENETICS
5
1. Pharmacogenetics assays: Providing an assay for clinical assessment of a
patient’s probable response to a drug is a major challenge in
pharmacogenetics. It includes;
• Improvement in a medically important response
• Limited false positives (efficacy-based assay)
• Limited false negatives (safety-based assay)
• Interpretable and clinically useful results
• Clinically validated results adequate for regulatory acceptance.
2. Pharmacogenetic Techniques
6. 6
GENETIC POLYMORPHISM IN DRUG
METABOLISM
Genetic polymorphism is the variations in DNA sequences. This explain
some of the variability in drug metabolizing enzyme activities which
contribute to,
Alteration in drug response
Impact patient’s response to drug therapy
Several extensively studied SNPs (single nucleotide polymorphism)
including the genes encoding for :
1. Glucose-6-phosphate dehydrogenase
2. N- acetyl transferase
3. The superfamily of Cytochrome P-450 (CYP) iso-enzymes.
7. CYTOCHROME P- 450 ISOENZYMES
7
Many hepatic cytochrome P–450 enzymes play an important role in the
oxidative biotransformation of numerous drugs and other foreign
compounds, and of many endogenous substrates.
In humans more than 20 different iso-enzymes of cytochrome P- 450
responsible for the hepatic metabolism of drugs, have been identified.
They are classified into families and sub families on the basis of the degree
of amino acid similarity.
Cytochrome P450 isoenzymes are regulated by both genetic and envi-
ronmental factors.
Of particular interest is genetic polymorphism in drug oxidation.
8. 8
Two genetic polymorphisms in drug oxidation are well known, the
sparteine/debrisoquine (CYP2D6) polymorphism and the mephenytoin
oxidation (CYP2C19) polymorphism.
As a result of these polymorphisms, two phenotypes exist in the population,
poor and extensive metabolizers.
Poor metabolizers may be prone to adverse reactions towards drugs with a
narrow therapeutic range.
In extensive metabolizers clinically significant drug interactions between
drugs metabolized by the same isoenzyme can occur.
Most oxidative processes take place in liver microsomes, a cellular fraction
derived from the endoplasmic reticulum, and are catalyzed by mono-
oxygenase enzymes known as mixed- function oxidases.
9. 9
The terminal oxidizing enzyme is cytochrome P-450, a hemoprotein.
The term "P450" refers to the ability of the reduced (ferrous) form of the
hemoprotein to react with carbon monoxide, yielding a complex with an
absorption peak at 450 nm.
The term "Cytochrome P-450" refers not to one enzyme: more than 20
different P-450 isoenzymes have been identified in humans.
P-450 isoenzymes are grouped in families within which the amino acid se-
quence homology is higher than 36%; they are designated by an Arabic
number.
The majority of P-450 isoenzymes involved in drug metabolism belong to
the CYP1, CYP2 and CYP3 families.
Each P-450 family is further divided into subfamilies, designated by capital
letters, which contain proteins that share more than 75% amino acid
sequence homology.
10. 10
A second Arabic number is used for the individual isoenzymes.
Cytochrome P – isoenzymes in Humans
CYP1A2, CYP2D6, CYP3A4 and CYP2C19 are important isoenzymes in
regard to drug metabolism in humans.
Different isoenzymes can be involved in the various steps of the metabolic
pathway of a drug.
11. 11
A particular step is often catalyzed by one isoenzyme, but in some cases
several isoenzymes can be involved.
Imipramine e.g. is hydroxylated by a single isoenzyme, CYP2D6, but is N-
de-methylated by at least three different isoenzymes (CYP1A2, CYP2C19,
CYP3A4).
12. 12
Drugs as substrates of specific Cytochrome P-450 isoenzymes
13. 13
GENETIC FACTORS INFLUENCING BIOTRANSFORMATION
It is known that interindividual differences in drug metabolism are largely
under genetic control.
For drugs such as phenylbutazone, nortriptyline and dicoumarol, important
differences in elimination rate can be seen within each pair of fraternal twins,
whereas within each pair of identical twins elimination rates are quite
similar.
Biotransformation is often under polygenetic control, and frequency
distribution plots of metabolic parameters usually yield continuous, uni-
modal curves.
For some drugs, however, metabolism is under monogenetic control and
shows a bimodal distribution, with genetic polymorphism in the population.
14. 14
Genetic polymorphism has first been described for a biotransformation
process which is not catalyzed by a cytochrome P-450 isoenzyme, the N-
acetylation of isoniazide and of a number of other drugs (e.g. procainamide,
hydralazine, dapsone, sulfadimidine).
Genetic polymorphism was later also recognized for drug oxidations, and
has, up until now, been described for CYP2D6 and CYP2C19.
The CYP2D6 polymorphism
This is often called the debrisoquine/sparteine polymorphism, for the two
classical probes used to study this polymorphism.
Because in some countries debrisoquine and sparteine are not available,
dextromethorphan, a commonly used cough suppressant drug, is used to
determine the CYP2D6 phenotype of an individual.
15. 15
CYP2D6 is primarily expressed in the liver.
It is also highly expressed in areas of the central nervous system, including
substantia nigra.
CYP2D6 is a 50-KD microsomal enzymes that metabolizes at least 25
different drugs including,
Anti-hypertensive agents
β-blockers
Anti-arrhythmic drugs
Anti-depressants
16. 16
CYP2C9 Genes
The CYP2C9 genes provides instructions for making an enzymes that is found
in a cell structure called the endoplasmic reticulum which is involved in protein
processing & transport.
They breakdown compounds including steroid hormones & fatty acids.
They play a major role in breaking down the drug Warfarin, which thin the
blood & prevent blood clots from forming.
This enzyme also assists in metabolizing other drugs such as Ibuprofen, which
reduces inflammation.
17. 17
CYP1A2 Genes
Another isoenzyme, which metabolizes 5% of randomly selected drugs.
The protein encoded by this genes localizes to the endoplasmic reticulum &
its expression is induced by some polycyclic aromatic hydrocarbon, some of
which are found in cigarette smoke.
It is able to metabolize some PAHs to carcinogenic intermediates.
Other xenobiotic substrates for this enzymes include caffeine, aflatoxin B1 &
acetaminophen.
18. 18
CYPC19 Genes
The CYP2C19 enzyme play a role in the processing or metabolizing of at
least 10% of commonly prescribed drugs. Eg : clopidogrel
It is an anti-platelet drugs which means that it prevents blood cells called
platelets from sticking together & forming blood clots.
The CYP2C19 enzyme converts clopidogrel to its active forms, which is
necessary for the drug to function in the body.
19. 19
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Cathygen H Dang https//www.ncbi.nlm.nih.gov/pmc/articles/pmc4093435
Harburoside press. Published in : 2013 July 2)
2. https://www.slideshare.net/mobile/rumanahameed1/drugtransport-and-drug
targeting-rumana-hameed.
3. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2014592/
4. Cytochrome P450: Genetic Polymorphism and Drug Interactions: F.M.
Belpaire & M.G. Bogaert,
http://dx.doi.org/10.1080/22953337.1996.11718518
5. Genetic Basis of Drug Metabolism: Margaret K. Ma, Michael H. Woo,
Howard L. Mcleod, Am J Health Syst Pharm. 2002;59(21),
https://www.medscape.com/viewarticle/444804_5.