What is pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to drugs
- How Genetic determinants and variability effect the way in which a drug works.
- Control for this to ensure efficacy and reduce side effects.
Tell me about the priniciples of drug action and the outcome of pharmacokinetic and pharmacodynamics
What are some drug determinants expressed as and what is this?
Several drug determinants expressed as Mendelian traits
A mendelian trait is Mendelian Traits are those traits which follow Mendel’s rules of only 2 possible versions of a gene (1 dominant, 1 recessive)
Give an example of a drug that is expressed as mendelian traits
Succinylcholine (Suxamethonium) neuromuscular junction block.
Tell me about Succinylcholine (Suxamethonium) neuromuscular junction block…
- Short lived drug used as muscle relaxant to immobilize in surgery.
- Short lived (thus controlled by its breakdown by serum cholinesterase).
- 1:3000 have a genetically altered enzyme that has reduced activity.
- The homozygous and heterozygous unaffected copy of gene enzyme activity.
- The individuals carrying two copies of the modified gene have adverse reaction.
- sustained neuromuscular junction muscle block.
Tell me about human genome variation
varies between individuals or every 500 or so nucleotides
- e.g. 14 million Single Nucleotide Polymorphisms (SNP) across the 3.2 billion nucleotides (3.2 Gigabases).
- Not all variations are functionally relevant but enough are to contribute variability
functional consequences of some genome variation
Genomic modulation of pharmacokinetic parameters. Cytochrome P450 (Cyp family). Tell me about some of the functions of this family…
- Major route for drug metabolism
- Essentially detoxifying oxidation reactions (other physiological functions).
- Transform drug structure to increase elimination.
- Transform drug structure to inactivate or reduce potency.
- Transform drug structure to increase potency relative to the parent (pro drug activation).
- Transform drug structure to generate toxic intermediate.
Some genomic changes that exist, for example P450
Spectrum of pharmacogenomic consequences
- Cytochrome P450 2D6 (CYP2D6)
- Chromosome 22 position q13.1
- Nine exons and eight introns
- >100 genetic variants across the gene.
- Important substrates tricyclic and selective
- serotonin reuptake blockers (antidepressants),
- Beta adrenergic receptor blockers, antiarrhythmic drugs.
- >10 fold variability in plasma concentrations.
- UM have very reduced levels of active drug- problem if there is a narrow therapeutic window.
- PM excess
- Increases pro-drug metabolism e.g. codeine
- to morphine: latter more potent and CYP2D6
- effects analgesia PM don’t use/UM overdose
Genetic variation in the drug targets. Clinically relevent pharmacodynamics determinant
Modified signalling in the Arg389Gly Beta 1 receptor
What are beta blockers useful for?
- after heart attack
- used in hypertension
Pharmacogenomic significance but complicated example…
After heart attack Beta blockers are used and helpful.
- Compare Arg389 and Gly389 cohorts there is a benefit to Arg 389.
- This outcome only seen if the comparison is made between treated and untreated
Beta blockers are used in hypertension.
- Compare Arg 389 and Gly 389 cohorts there is a benefit to Arg 389
- Again, most striking (clinically relevant) if compare treated and untreated.
- Supports drug induced mitigation against underlying susceptibility.
- Genetic profiling might highlight cohorts that best served by given drug treatment.
Aims pharmacology 2020
- Introduce the idea of receptor families.
- Describe how gene cloning and most recently genome sequencing have expanded view of receptor families.
- Describe some of the better characterized receptor families and list aspects of their structure function activity.
- Use GPCR adrenergic receptor and nicotinic acetylcholine receptors to detail how current and emerging structures inform on protein conformations that allow receptor function.
- Describe principles of tyrosine kinases and steroid receptors.
- Introduce the key principles Pharmacogenomics.
- Use examples of how genetic determinants effect drugs by changing their Pharmacokinetics and Pharmacodynamics.
