Pharmacogenomics 1 Flashcards

1
Q

define: pharmacogenomics

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

how is genotype-phenotype involved in pharmacogenomics?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what stages in drug metabolism can be flawed ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is biochemical modification of a drug ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what are the different variations in drug response ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

describe succinylcholine sensitivity:

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

describe malignant hyperthermia

A

= 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what are the treatments for malignant hyperthermia ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

how is alcohol metabolised ?

A

alcohol to acetylaldehyde by alcohol dehydrogenase

acetylaldehyde to acetic acid by aldehyde dehydrogenase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

why are some individuals more tolerable to alcohol?

A

because they have more alcohol dehydrogenase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is aldehyde dehydrogenase dysfunction ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is aversive therapy?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

how can polymorphisms affect GPCRs?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is glucose-6-phosphate dehydrogenase ?

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is the link between antimalarial drugs and G6PD?

A

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

17
Q

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

A

evolved mechanisms are already in place

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

18
Q

define:Pharmacogenetics

A

genetic variation revealed solely by the effects of drugs

19
Q

what is ecogenetics ?

A

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

20
Q

what are the benefits of pharmacogenomics?

A
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
21
Q

how can more powerful medicines be produced by pharmacogenomics?

A

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

22
Q

how can pharmacogenomics produce better and safer drugs ?

A

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

23
Q

how will pharacogenomics affect drug dosages ?

A

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

24
Q

how is advanced warning contributing to pharmacogenomics?

A

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

25
Q

how can better vaccines be produced by pharmacogenomics?

A

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

26
Q

how will pharmacogenomics improve drug discovery |?

A

new easier to find therapeutics targetting the genome

drug trials will be more focussed for a specific population

27
Q

how will pharmacogenomics decrease cost of health care ?

A

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

28
Q

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

A

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

29
Q

what are the examples for genetic variation in drug response ?

A

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

30
Q

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

A

produce sensitivity/resistance