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
