Pharmacogenomics 1 Flashcards
define: pharmacogenomics
development of new drugs from discover of new genes/pathways, possibility of creating personalised drugs for individuals based on their own genetic make-up
- tailoring drugs to specific individuals or subpopulations
- subpopulations is more likely and it is importnat in diseases caused by polygenic effects
how is genotype-phenotype involved in pharmacogenomics?
correlation between clinical manifestations of many genetic disorders
for a target to be pharmacologically important differences must affect the function or amount of a protein
drug sensitivity/resistance can be genetic
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what stages in drug metabolism can be flawed ?
all stages can be flawed
individuals will have different metabolisms - therefore to design drugs for an individual it would be difficult to determine where a fault may be
what is biochemical modification of a drug ?
many drugs are biochemically modified to increase excretion -increase solubility
often conjugated with glucuronic acid in the liver
can be acetylated by addition of acetyl group into the molecule
what are the different variations in drug response ?
CONTINUOUS VARIATION= polygenic- normal distribution, no particular gene affecting it
BIOMODEL DISTRIBUTION- 2 ways it is metabolised- there is a dominant and a recessive form
TRIMODEL DISTRIBUTION- 3 ways, RR, Rr, rr
describe succinylcholine sensitivity:
suxamethonium- depolarising neuromuscular blocking agent
- normal short acting =10mins so its used for rapid procedures- anaesthetic
- 1 in 2000 people will get apnoea for more than 1 hour
- prolonged paralysis- abnormal plasma cholineesterase (this can last 2 hours but if enzyme is absent it lasts longer)- checking enzyme levels is a pharmacogenetic approach already in clinical practice
- can be fatal when sensitivit is inherited in an autosomal recessive manner
describe malignant hyperthermia
= rigidity, severe hyperthermia (42.3), acidosis, tachycardia and 65% mortality
- usually occurs when given in combination with halogenated general anaesthesia such as halothene
- it is an autosomal dominant trait determined by muscle biopsy and response to halothene
- some cases it is caused by a mutation in a gene coding for skeletal muscle ryanodine receptor channel that mediates calcium release in the SR
- very heterogenous= many genes linked to the disorder
what are the treatments for malignant hyperthermia ?
cooling
100% oxygen
treatment for acidosis and admin dantrlenne which blocks calcium release via ryanodine receptors
how is alcohol metabolised ?
alcohol to acetylaldehyde by alcohol dehydrogenase
acetylaldehyde to acetic acid by aldehyde dehydrogenase
why are some individuals more tolerable to alcohol?
because they have more alcohol dehydrogenase
what is aldehyde dehydrogenase dysfunction ?
ALDH2- is shown in some populations
it causes acetylaldehyde to build up which is toxic aand causes flushing, hyperventilation, panic, tachycardia
this enzyme cannot be induced
what is aversive therapy?
used to treat alcoholism
uses disulfiram- it is stuck in the stomach and is an ALDH inhibiter therefore alcoholics suffer horrible side effects when taking alcohol to help them to stop taking it
what are beta blocker important for and what do they bind to ?
bind to GPCRs
treat HF
metaprolol, bisoprolol and carvedilol
responses to beta blcokers are variable among patients wth HF - thought that polymorphisms contribute
how can polymorphisms affect GPCRs?
they can cause silent mutations but some cause missense polymorphisms and altered amino acid sequences are produced
what is glucose-6-phosphate dehydrogenase ?
it is the most common human enzyme deficiency - 400 million people affected- mainly in malaria infected places such as africa, mediterranean, middle east
- it is x linked recessive so males are more likely to have it
- they have less glutathione so the red blood cells are less protected from free radicals