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
L
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
what is the link between antimalarial drugs and G6PD?
primaquine is an antimalarial drug which target hepatic stage of parasite- it depletes RBCs
therefore a deficiency of G6PD may confer protection against malaria - could be an evolutionary advantage in endemic areas
what is the link between evolution and variation in drug response ?
evolved mechanisms are already in place
no clear reason why but it is probably due to selective advantage
define:Pharmacogenetics
genetic variation revealed solely by the effects of drugs
what is ecogenetics ?
genetically determined differences in susceptibility to action of physical, chemical and infectious agents in the environment
e.g uv light is an environmental agent and people with fair skin have a greater genetic susceptibility leading to skin cancer
fat is an environmental agent within foods and people with hypercholesterolamia have a higher susceptibility to them causing atherosclerosis
what are the benefits of pharmacogenomics?
more powerful medicines better, safer drugs drug dosage can be more accurate advanced warning of diseases better vaccines improvement in drug discovery decrease in cost of health care
how can more powerful medicines be produced by pharmacogenomics?
these medicines can be based on the individuals proteins, enzymes and RNA that is associated with genes and diseases- therefore the drug will target a specific disease more efficiently
how can pharmacogenomics produce better and safer drugs ?
there will be less trial and error
the drug will be matched to the genetic profile of the individual- this should speed up recovery time and increase safety
how will pharacogenomics affect drug dosages ?
instead of taking dose based on weight and age, it will be based on the individuals ADME -this should minimise overdose and maximise therapy
how is advanced warning contributing to pharmacogenomics?
knowledge of genetic code will allow precautionary measures such as screening to be performed earlier
how can better vaccines be produced by pharmacogenomics?
the vaccines can be made of genetic material which reduces risk
- activate the immune system without causing infection
how will pharmacogenomics improve drug discovery |?
new easier to find therapeutics targetting the genome
drug trials will be more focussed for a specific population
how will pharmacogenomics decrease cost of health care ?
decrease in adverse reactions
decrease in medication duration
decrease in failed courses of medication
diseases can be caught earlier
what differences could the genetic polymorphisms cause to contribut to the variability in responses to beta-blockers ?
left ventricular ejection fraction improvement
survival
hospitalisation due to sympton exacerbation
respiratory differences in beta 2 adrenoreceptors
what are the examples for genetic variation in drug response ?
succinylcholine sensitivity- issues in anaesthesia
malignant hyperthermia- in operations dues to halothane sensitivity
ethanol- effects on ADH and effects on metabolism of acetylaldehyde
GPCR dysfunctions- differences in effects of beta blockers
glucose-6-phosphate dehydrogenase- haemolytic anaemia due to exidative stress
what can lack of or excessive activity of biochemical modifications cause?
produce sensitivity/resistance
