Pharmacogenetics and Pharmacogenomics

?
  • Created by: LBCW0502
  • Created on: 14-12-19 12:16
How can you screen for pharmacogenetic polymorphisms?
Screen alleles (e.g. type of metabolism, presence of alleles such as CYP2C9 etc)
1 of 50
What considerations must be taken into account when prescribing prodrugs?
Genetics, patient characteristics (e.g. ethnicity), polypharmacy etc
2 of 50
Give examples of drugs discovered using genomics
MLN4760 (treat obesity, ACE2-I, reduce BP). PKC412 (acute myeloid leukaemia and mixed lineage leukaemia, protein tyrosine kinase inhibitor). ABthrax (inhibits function of anthrax protective antigen - facilitates progression of anthrax infection)
3 of 50
Give examples of drugs whose efficacy is affected by a patient's pharmacogenetics (1)
Albuterol (treat asthma, polymorphisms in b2 adrenergic receptor). Gefitinib (for lung cancer, inhibitor of EGFR, upregulate lung cancer tissue, efficacy not good, mutation frequencies)
4 of 50
Give examples of drugs whose efficacy is affected by a patient's pharmacogenetics (2)
Panitumamab (treat metastatic colcorectal cancer, anti-EGFR antibody)
5 of 50
What is a genome?
An organism's complete set of genes and chromosomes
6 of 50
What is the definition of genomics?
The process of mapping, sequencing and analysing genomes
7 of 50
What is pharmacogenomics?
An individual patient's genetic profile for disease and genetic interaction
8 of 50
Describe features of the human genome (1)
3 billion base pairs, only 2% encodes genes, approx 22,300 genes, more than 10^6 mRNA transcripts, more than 10^7 genetic polymorphisms. Human genome contained in nucleus. Majority of genes have no function (exceptions - introns). Mutations
9 of 50
Describe features of the human genome (2)
Large genome, junk DNA, mutation likely to go into 'junk' DNA/non-coding region rather than DNA which encode genes. Background radiation (e.g. radon) - ionise DNA, mutations. Number of genes doesn't indicate complexity of organism
10 of 50
Describe features of the human genome (3)
Genes can make several different forms of proteins (mRNA transcripts). Identical twins, different base pair/genes. Genome produces proteome
11 of 50
Describe features of the human genome project (1)
Launched in 1990s, completed in April 2003. Multinational effort involving 20 research institutions. Public and privately funded. Variety of samples used e.g. ethnicity, age, gender. 3 stages - generation of chromosome maps
12 of 50
Describe features of the human genome project (2)
Large scale DNA sequencing, annotation of sequence. 1st chromosome (22) completed in 1999. Consensus sequence - most common base at each position, wild type. No one has consensus sequence (mutant) - no perfectly functioning genes
13 of 50
Describe the information obtained from the HGP (1)
Place sequences in groups, combined to determine chromosome. Work out role of genes, interactions, role in disease. Don't know all sequences - caps, hypervariable, genes involved in immunoglobulins (hypervariable, difficult to sequence areas)
14 of 50
Describe the information obtained from the HGP (2)
mRNS, splicing, create different proteins from the same sequence. DNA makes copies of itself in the sequence. (Scale of human genome - very large)
15 of 50
Describe the information obtained from the HGP (3)
Objectives - role of gene products, control of genes, interactions, involvement in human disease. Identity of 90% of genes known. Structure/function of 75% of these are known. Alternate splicing. 40 genes obtained directly from bacteria
16 of 50
Describe the information obtained from the HGP (4)
Only 7% of protein families are vertebrate specific. 40% of DNA is repetitive. Single Nucleotide Polymorphisms (SNPs) - most common polymorphism (1.4m), 1 every 300-1000 bp (depends on sequence)
17 of 50
Describe the information obtained from the HGP (5)
SNPs define individuality, most neutral, many disease-causing
18 of 50
Describe features of SNPs (1)
Single nucleotide changes at a single point, effect depends on location in the codon. 1st/2nd/3rd codon. 3rd codon mutation - no change in amino acid, redundant. 2nd codon - little/no change. 1st codon - change.
19 of 50
Describe features of SNPs (2)
Open reading frame - 3rd base of codon mutation is ok
20 of 50
Describe features of haplotypes (1)
Different SNPs/mutations that move together during genetic recombination (produce gametes), linked to certain ethnicities (a certain ethnicity has a certain haplotype). DNA testing (ethics). Ancestry
21 of 50
Describe features of haplotypes and malignant melanoma
Cancer detection. Malignant melanoma – genotype them, observe different genetics, respond differently to different drugs. Tumours grouped together. Identify group – similar treatment. Able to match treatment to groups of tumours
22 of 50
Describe features of using genomics in the drug discovery pipeline (1)
Determine efficacy of treatments. Genomics used to rapidly increase drugs to the market stage. Use genomics to identify patients who don’t respond to drug or patients respond to drug. Stop getting drug to the market if not effective
23 of 50
Describe features of using genomics in the drug discovery pipeline (2)
Able to market the drug for particular patients. Cheaper in drug discovery pipeline. Reduce risk of patients dying when drug gets to market with ADRs/side-effects
24 of 50
Describe features of inter-individual variability (1)
Most populations show large inter-individual variability in drug response and toxicity to all major classes of drugs given at standard dose. Genetic factors estimated to account for 15-30% of inter-individual differences in drug metabolism/response
25 of 50
Describe features of inter-individual variability (2)
For certain drugs, genetic factors can account for up to 95% of inter-individual variability in drug disposition and effects
26 of 50
Describe features of pharmacogenetics vs pharmacogenomics (1)
Pharmacogenetics, single gene variants, large effect, limited number of people, make decision if drug is suitable for patient based on their genetics. Pharmacogenomics, many genomic loci, large biochemical pathways, small effect, large no. of people
27 of 50
Describe features of pharmacogenetics vs pharmacogenomics (2)
Pharmacogenetics, large effect on limited number of people due to single gene variants, effective or not, toxicity
28 of 50
Describe features of pharmacogenetics vs pharmacogenomics (3)
Pharmacogenomics - number of drugs involved, gives variation in people, range of patient response due to individual input of targets, e.g. enzymes, efficacy. Pharmacogenetics deals with drug toxicity, pharmacogenomics deals with patient response
29 of 50
Describe features of pharmacogenomic screening (1)
Two copies of genotype. Combined effectiveness gives phenotype – split into three different types. Extensive metabolisers (80-65%) – two copies of gene (drug absorbed, expected response/metabolism, suitable for drugs)
30 of 50
Describe features of pharmacogenomic screening (2)
Intermediate metabolisers, 10-15% – one defective copy, exaggerated response due to drug reaching toxic plasma levels, longer half-life, not metabolised quickly. Poor metabolisers – high plasma conc, serious adverse reaction, long time for metabolism
31 of 50
Describe features of pharmacogenomic screening (3)
Prodrug – no response in poor metabolisers (5-10%), same/effective response in extensive metabolisers.
32 of 50
Describe features of pharmacogenomic screening (4)
CYP2D6 – ultra-rapid metabolizer, concentration doesn’t reach therapeutic window, drug not effective for patient, pro-drug (high concentration of drug e.g. codeine – could cause respiratory depression, common in African ethnicity).
33 of 50
What is the phenotype distribution for CYP2D6?
Majority are extensive metabolisers (few cases for other categories
34 of 50
Describe features of metoprolol and CYP2D6
PM has a higher plasma PK compared to EM (higher HR in PM compared to EM, drug more effective due to not being metabolised)
35 of 50
Describe features of CYP2D6 and dose adjustment
Genetics can cause a drug to work too well, cause toxicity. Able to adjust dose. May need to get a patient genetically tested
36 of 50
Describe features of CYP2D6 and pharmacological consequences (1)
Taxol, Caucasian patients (enzyme, polymorphism). E.g. reduce dose of imipramine (metabolised by CYP2D6), consider alternative, inform patient about side effects. People taking narcotics can knock out their CYP2D6
37 of 50
Describe features of CYP2D6 and pharmacological consequences (2)
(drug-drug interaction, common in polypharmacy). Tamoxifen – prodrug, PM (more N-desmetTAM), EM (more endoxifen). Ultra-rapid or PM – not good metabolic rates
38 of 50
State features of CYP2C9 and metabolism of warfarin
Adjust dose of warfarin (first line). Patients may be on low doses of warfarin (variations in metabolism).
39 of 50
Describe features of NAT2 pharmacogenetics
Sulphonamides, sulphones (Dapsone), isoniazid (treat TB, acetylated, excreted out of urine). Fast acetylator (40% Caucasian, 85-90% Japanese, 30% Indian)
40 of 50
What are the consequences of NAT2 pharmacogenetics?
Fast metabolised – metabolite produced in high levels, kidney stones, acetyl group in aqueous environment (precipitate). Slow metaboliser – via CYP, hydroxylamine, if not excreted becomes oxidised, can cause kidney damage
41 of 50
Describe features of thiopurine S-methyltransferase
Childhood leukaemia – captopurines metabolised by TPMT. EM – can have normal dose. PM – normal dose cannot be used, high levels, suppress bone marrow too far, myelosuppression. Most clinics genotype children prior to leukaemia treatment due to S/E
42 of 50
Describe the pharmacogenetics (1)
PMs may be more susceptible to toxicity due to elevated plasma concentrations – in particular drugs with narrow TI, e.g. warfarin (titrate). EMs may be at risk of drug-drug interactions – not as serious as for PMs
43 of 50
Describe the pharmacogenetics (2)
UMs are at risk of prodrug toxicity – codeine. UMs also at risk of treatment failure – e.g. amitriptyline
44 of 50
Describe the polygenetic determinants of drug response (1)
Pharmacogenomics (how a drug works). Polymorphism of drug metabolising enzyme – 3 types. EM (70%, small amount of drug in plasma), IM (35%, greater level of active drug), PM (1%, highest level)
45 of 50
Describe the polygenetic determinants of drug response (2)
Drug receptor sensitivity. EM – 75% efficacy at that concentration, low toxicity (1%), therapeutic ratio of 75 (efficacy : toxicity), 10% response, therapeutic ratio of 10 (not toxic, not effective)
46 of 50
Describe the polygenetic determinants of drug response (3)
IM – higher concentration, 85% efficacy, 10% toxicity, therapeutic ratio decreases. PM – 95% efficacy but maximum toxicity, therapeutic ratio even smaller. Therapeutic ratio should be as large as possible – efficacy
47 of 50
Describe the polygenetic determinants of drug response (4)
UM, EM, PM. Extent of crossing BBB. Phenotypes of receptors (mutated or normal), transporter (re-uptake of drug), enzymes for metabolism. Determinants collectively give a response to a drug
48 of 50
Give examples of pharmacogenomics
MDR1 - drug transporter & HIV protease inhibitors. ADRB1 - b-receptor and b antagonists. ADRB2 - b-receptor and inhaled b agonists. ADD1 - diuretics. VKORC1 - warfarin and vitamin K epoxide reductase. CRHR1 - inhaled steroids
49 of 50
State features of individual variation and dose response phenotype
HT3 antagonist (tropisetrone) is a CYP2D6 substrate. HT3 antagonist (tropisetrone) is a MDR1 substrate. Genetic polymorphisms in TPH2 (tryptophan hydroxylase 2), SERT (high-affinity serotonin reuptake transporter), MAO (monoamine oxidase)
50 of 50

Other cards in this set

Card 2

Front

What considerations must be taken into account when prescribing prodrugs?

Back

Genetics, patient characteristics (e.g. ethnicity), polypharmacy etc

Card 3

Front

Give examples of drugs discovered using genomics

Back

Preview of the front of card 3

Card 4

Front

Give examples of drugs whose efficacy is affected by a patient's pharmacogenetics (1)

Back

Preview of the front of card 4

Card 5

Front

Give examples of drugs whose efficacy is affected by a patient's pharmacogenetics (2)

Back

Preview of the front of card 5
View more cards

Comments

No comments have yet been made

Similar Pharmacy resources:

See all Pharmacy resources »See all Pharmacogenetics and Pharmacogenomics resources »