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Pharmacogenomics(biotechnology)
1. An Assignment on
Pharmacogenomics
Submitted by
Roll:-14308
Reg:-1086
Date of Submission:-23/03/21
Submitted to
MD Abdul Kaium Siddiki
Lecturer
Department of Pharmacy,
University of Science and Technology
Chittagong (USTC)
Department of Pharmacy
Course Name: Pharmaceutical Biotechnology
Course No:-PHR-309
2. 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.
Pharmacogenetics is the study of how people respond differently to drug therapy
based upon their genetic makeup or genes. Diet, overall health, and environment
also have significant influence on medication response, but none are stronger
indicators of how you will process medication than your genetics.
Objectives of Pharmacogenomics:-
Introduction
3. Improve drug safety, and reduce ADRs;
Tailor treatments to meet patients' unique genetic pre-disposition, identifying
optimal dosing;
Improve drug discovery targeted to human disease; and
Improve proof of principle for efficacy trials.
Goals of Pharmacogenomics:-
Understand polymorphism of drug metabolizing enzyme.
Transporter or receptor that ultimately determine the outcome of drug
therapy.
Pharmacogenomic Studies :-
Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and
other drug targets have been linked to inter individual differences in the efficacy
and toxicity of many medications.
Pharmacogenomic studies are rapidly elucidating the inherited nature of these
differences in drug disposition and effects, thereby enhancing drug discovery
and providing a stronger scientific basis for optimizing drug therapy on the basis of
each patient's genetic
constitution.Pharmacogenomic Studies Pharmacogenomics uses genome-wide
approaches to elucidate the inherited basis of differences between persons in
the response to drugs.
More than 1.4 million single-nucleotide polymorphisms were identified in the
initial sequencing of the human genome, with over 60,000 of them in the coding
region of genes.
4. 1. Single nucleotide polymorphism — one nucleotide base pair replaces
another
2. Insertion/deletions — nucleotide or nucleotide sequence is added
or deleted
3. Tandem repeats — nucleotide sequence repeats in tandem (e.g. AGA
GAG)
4. Frameshift mutation — an insertion/deletion mutation in which the change
in number of nucleotides is not a multiple of three
5. Defective splicing — internal polypeptide segment is abnormally removed
and remaining ends are joined
Examples of Gene Mutations
5. 6. Premature stop codon — premature termination of the polypeptide chain
7. Copy number variations — an abnormal number of copies of a gene
8. Polymorphisms — variation (mutation) in at least 1% of population .Eg.
Eye color , Hair color , Blood type and Drug metabolizing enzymes
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.
Fig:- DNA molecule 1 differs from DNA molecule 2 at a single base-pair location (a C/T)
Single Nucleotide Polymorphism (SNP):
6. a) Over 50 cytochrome P450 isoenzymes
Three families – CYP1, CYP2, CYP3
Fifteen known to metabolize drugs
At least seven with documented polymorphisms –CYP2A6, 2C9, 2C19,
2D6, 3A4/5, 1A2
b) Two copies of each gene encode for a CYP enzyme Each copy is referred to
as an allele
c) Example of a polymorphic CYP enzyme
Pharmacogenetics and CYP Enzyme
7. Enzyme involved in drug Metabolism:-
Case A – Antipsychotic adverse reaction:-
Patient A suffers from schizophrenia. Their treatment included a combination of
ziprasidone, olanzapine, trazodone and benztropine. The patient experienced
dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and
transitioned to quetiapine. Trazodone was discontinued. The patient then
experienced excessive sweating, tachycardia and neck pain, gained considerable
weight and had hallucinations. Five months later, quetiapine was tapered and
discontinued, with ziprasidone re-introduction into their treatment due to the
excessive weight gain. Although the patient lost the excessive weight they gained,
they then developed muscle stiffness, cogwheeling, tremors and night sweats.
Examples and case study
8. When benztropine was added they experienced blurry vision. After an additional
five months, the patient was switched from ziprasidone to aripiprazole. Over the
course of 8 months, patient A gradually experienced more weight gain, sedation,
developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular
movements. A pharmacogenomics test later proved the patient had a CYP2D6
*1/*41, which has a predicted phenotype of IM and CYP2C19 *1/*2 with a
predicted phenotype of IM as well.
Case B – Pain Management:
Patient B is a woman who gave birth by caesarian section. Her physician
prescribed codeine for post-caesarian pain. She took the standard prescribed dose,
however experienced nausea and dizziness while she was taking codeine. She also
noticed that her breastfed infant was lethargic and feeding poorly. When the patient
mentioned these symptoms to her physician, they recommended that she
discontinue codeine use. Within a few days, both the patient and her infant's
symptoms were no longer present. It is assumed that if the patient underwent a
pharmacogenomic test, it would have revealed she may have had a duplication of
the gene CYP2D6 placing her in the Ultra-rapid metabolizer (UM) category,
explaining her ADRs to codeine use.
Case C – FDA Warning on Codeine Overdose for Infants
On February 20, 2013, the FDA released a statement addressing a serious concern
regarding the connection between children who are known as CYP2D6 UM and
fatal reactions to codeine following tonsillectomy and/or adenoidectomy (surgery
to remove the tonsils and/or adenoids). They released their strongest Boxed
Warning to elucidate the dangers of CYP2D6 UMs consuming codeine. Codeine is
converted to morphine by CYP2D6, and those who have UM phenotypes are at
danger of producing large amounts of morphine due to the increased function of
the gene. The morphine can elevate to life-threatening or fatal amounts, as became
evident with the death of three children in August 2012.
Conclusion:-
• Genetic variation contributes to inter-individual differences in drug response
phenotype at every pharmacologic step
• Through individualized treatments, pharmacogenetics and pharmacogenomics are
expected to lead to:
o Better, safer drugs the first time
o More accurate methods of determining appropriate drug dosages
9. • Pharmacogenomics offers unprecedented opportunities to understand the genetic
architecture of drug response
References:-
Ermak, Gennady (2015). Emerging Medical Technologies. World
Scientific. ISBN 978-981-4675-80-2.
Johnson JA (November 2003). "Pharmacogenetics: potential for
individualized drug therapy through genetics". Trends Genet. 19 (11):
660–6. doi:10.1016/j.tig.2003.09.008. PMID 14585618.
Becquemont L (June 2009). "Pharmacogenomics of adverse drug reactions:
practical applications and perspectives". Pharmacogenomics. 10 (6): 961–
9. doi:10.2217/pgs.09.37. PMID 19530963.
Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C,
Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP (August
2010). "Realities and expectations of pharmacogenomics and personalized
medicine: impact of translating genetic knowledge into clinical
practice". Pharmacogenomics. 11 (8):114967. doi:10.2217/pgs.10.97. PMI
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