Week 1 Flashcards
Pharmacogenetics definition and use
- Influence genes on the efficiency and side effects of drugs.
- Variable response due to individual gene(s)
Phamacogenomics definition and use
- describes the interaction between drugs and the whole genome
- Variable response due to multiple loci across the genome
Five stages following drug administration
- Absorption into the body
- Distribution to the site of action
- Target integration e.g. binding to cellular receptors or ion channels
- Metabolic processing
- Excretion - From the body
What are the most influential genes when studying variation in drug responses?
- Those influencing Pharmacokinetic properties, the drug metabolising enzymes and transporters, effecting how the drug is handled in the body.
- Those influencing Pharmacodynamic properties, including drug targets; enzymes, receptors and ion channels, and associated pathways determining the drugs effect in the body.
Example of a gene which effects the Pharmacokinetic drug properties
The ABCB1 gene encoding for the MDR1 drug transporter, variants of the gene are associated with the resistance to the effects of drugs such as the anti-epileptic agent phenytoin.
Example of a gene which effects the Pharmacodynamic drug properties
The CYP2C19 gene encoding metabolic enzyme cytochrome p450. Variants of the gene are associated with decreased responsiveness to omeprazole used to treat peptic ulcers and other gastric complaints.
What is the most common genetic variant which affect drug action?
SNPs Single nucleotide polymorphisms which substitutes one base for another. when there are sets of closely linked SNPs are called haplotypes.
If there are two common variants C or T at a specific position in a multi drug transporter gene ABCB1. How could this effect how the drug effects people.
Different people would have different genotypes for example CC CT or TT, these genotypes could be link to resistance or enhancement of the administered drug.
Efficacy definition
Maximum beneficial or therapeutic response that a drug can produce and is a measure of clinical effectiveness. It can be expressed in percentage who show a therapeutic response at a given, standard dose.
Toxicity
The extent of a drug inducing unwanted or harmful side effects.
- Expressed as the percentage of patients who show adverse side effects at a given dose.
The optimal dose range
- Is that at which the efficacy is greatest and toxicity is lowest.
- Extreme drug responders such as:
- Non-responders - drug ineffective
- Adverse responders - causes major harmful side effects.
Cancer therapeutics
Means that we can look at the specific differences between healthy and cancerous cells, meaning the differences can be exploited to target therapeutics.
The issues with chemotherapy
To achieve reasonable efficacy, a substantial degree of toxicity is required.
What is Herceptin?
- Which is an antibody-based therapeutic used for the treatment of HER2 positive breast cancers.
- Normally HER2 is bound to by grown factors but Herceptin, competitively binds known as a blocking growth factor.
What are CPIC Guidelines used for?
To help clinicians understand how available genetics test results can be used to optimise drug therapy.
Absorption
The movement of a drug from its site of administration into the system circulation.
Active drug
The drug takes effect immediately. e.g. Morphine
Adverse drug reaction
An unintentional, harmful reaction to medicines.
ADME
Absorption, distribution, metabolism and elimination (the key components of pharmacokinetics)
Allele
One of two or more single forms of a gene.
Base pair
Two nucleotides on complementary DNA strands.
Candidate gene
A gene predicted to be associated with a particular trait e.g disease, adverse reaction to a drug.
Cytochrome P450
A group of enzymes involved in drug metabolism and found in high levels in the liver. These enzymes change many drugs, including anti-cancer drugs, into less toxic forms that are easier for the body to excrete. Examples include CYP2D6, CYP2C19 and CYP2C9
DNA
(Deoxyribonucleic acid) carries genetic instructions for all living things
Enzyme
A biologists catalyst, usually a protein which speeds up the rate of a specific chemical reaction, each specific.
Excretion
A pharmacokinetic term that refers to removal of a drug in the unchanged form. Excretion along with metabolism, account for the drug elimination.
Exome
Part of the genome formed by DNA sequences that encodes genes (exons)
Genes
The basic physical unit of inheritance
Genotype
An individuals collection of genes
GWAS
- Study common genetic variations across the genome of a large population
- To see if investigated variations are associated with a phenotype of interest
Haplotype
Collection of genetic variants that travel together on the same allele. E.g. SNP
Heterozygosity
When two different alleles are present on a chromosome pair
Homozygosity
When two identical alleles are present on the chromosome pair
Poor metaboliser
Have two non-functional alleles and therefore have little to enzyme activity.
Intermediate metaboliser
Have one non-functional allele and one normally functioning allele and therefore have decreased enzymes activity.
Extensive metaboliser
They have 2 normally functioning alleles, and therefore have normal enzyme activity.
Ultra-Rapid metabolisers
Have one or more alleles which results in increased enzyme activity compared to extensive metabolisers.
Nucleotides
The building blocks of DNA. Four nucleotides make up DNA: Adenine (A), Cytosine, (C), Guanine (G) and Thymine (T).
Phase I metabolism
Chemical changes - compound more hydrophilic
- so it can be eliminated by the kidneys.
- Reactions usually involve either adding or unmasking a
hydroxyl group
- usually involve hydrolysis, oxidation or reduction mechanisms.
Phase II metabolism
Takes place if phase I is insufficient or if it creased a reactive metabolite
- Clear a compound from circulation
- Reactions involve adding large polar group (conjugation reaction) increasing the compounds solubility.
- Functional groups generated in phase I reactions are required for polar group attachment.
Phase III
- Involves drug transporters which moves drugs across cellular barriers, meaning accumulation at target site.
- Influencing absorption, distribution and elimination of a drug.
Location: epithelial and endothelial cells of the liver, gastrointestinal tract, kidneys, blood-brain barrier.
Phenotype
Observable physical characteristics
Polymorphism
A variant that has two or more alleles and is present at a frequency of at least 1% of the population.
Prodrug
A precursor of a drug. A prodrug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent .
SNPs
A single nucleotide locus with two or more naturally occurring alleles defined by a single base pair substitution.
What converts codine into its active metabolite?
CYP2D6 converts Codine into morphine its active metabolite
Whats an example of a polar group?
glucuronide
What enzymes are responsible for phase I reactions?
Cytochrome P450 enzymes
What enzymes are responsible for phase II reactions?
Transferase enzymes
