Pharmacogenomics 1

Question 1

define: pharmacogenomics

Answer 1

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

Question 2

how is genotype-phenotype involved in pharmacogenomics?

Answer 2

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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Question 3

what stages in drug metabolism can be flawed ?

Answer 3

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

Question 4

what is biochemical modification of a drug ?

Answer 4

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

Question 5

what are the different variations in drug response ?

Answer 5

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

Question 6

describe succinylcholine sensitivity:

Answer 6

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

Question 7

describe malignant hyperthermia

Answer 7

= 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

Question 8

what are the treatments for malignant hyperthermia ?

Answer 8

cooling
100% oxygen
treatment for acidosis and admin dantrlenne which blocks calcium release via ryanodine receptors

Question 9

how is alcohol metabolised ?

Answer 9

alcohol to acetylaldehyde by alcohol dehydrogenase

acetylaldehyde to acetic acid by aldehyde dehydrogenase

Question 10

why are some individuals more tolerable to alcohol?

Answer 10

because they have more alcohol dehydrogenase

Question 11

what is aldehyde dehydrogenase dysfunction ?

Answer 11

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

Question 12

what is aversive therapy?

Answer 12

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

Question 13

what are beta blocker important for and what do they bind to ?

Answer 13

bind to GPCRs
treat HF
metaprolol, bisoprolol and carvedilol
responses to beta blcokers are variable among patients wth HF - thought that polymorphisms contribute

Question 14

how can polymorphisms affect GPCRs?

Answer 14

they can cause silent mutations but some cause missense polymorphisms and altered amino acid sequences are produced

Question 15

what is glucose-6-phosphate dehydrogenase ?

Answer 15

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

Question 16

what is the link between antimalarial drugs and G6PD?

Answer 16

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

Question 17

what is the link between evolution and variation in drug response ?

Answer 17

evolved mechanisms are already in place

no clear reason why but it is probably due to selective advantage

Question 18

define:Pharmacogenetics

Answer 18

genetic variation revealed solely by the effects of drugs

Question 19

what is ecogenetics ?

Answer 19

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

Question 20

what are the benefits of pharmacogenomics?

Answer 20

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

Question 21

how can more powerful medicines be produced by pharmacogenomics?

Answer 21

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

Question 22

how can pharmacogenomics produce better and safer drugs ?

Answer 22

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

Question 23

how will pharacogenomics affect drug dosages ?

Answer 23

instead of taking dose based on weight and age, it will be based on the individuals ADME -this should minimise overdose and maximise therapy

Question 24

how is advanced warning contributing to pharmacogenomics?

Answer 24

knowledge of genetic code will allow precautionary measures such as screening to be performed earlier

Question 25

how can better vaccines be produced by pharmacogenomics?

Answer 25

the vaccines can be made of genetic material which reduces risk
- activate the immune system without causing infection

Question 26

how will pharmacogenomics improve drug discovery |?

Answer 26

new easier to find therapeutics targetting the genome

drug trials will be more focussed for a specific population

Question 27

how will pharmacogenomics decrease cost of health care ?

Answer 27

decrease in adverse reactions
decrease in medication duration
decrease in failed courses of medication
diseases can be caught earlier

Question 28

what differences could the genetic polymorphisms cause to contribut to the variability in responses to beta-blockers ?

Answer 28

left ventricular ejection fraction improvement
survival
hospitalisation due to sympton exacerbation
respiratory differences in beta 2 adrenoreceptors

Question 29

what are the examples for genetic variation in drug response ?

Answer 29

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

Question 30

what can lack of or excessive activity of biochemical modifications cause?

Answer 30

produce sensitivity/resistance