Tutorial: Variability in human responses to drugs

Question 1

How can absolute differences in an administered drug dose occur?

Answer 1

Absolute difference= the actual dose given is different due to

1. a) error in prescription or dispensing
   b) patient non-compliance
   c) drug formulation

Question 2

Explain how envoronemntal exposure to drugs or chemicals can alter relative drug dosage?

Answer 2

E.g. they can

• enzyme induction (increase rate of metabolism)
• enzyme inhibition (decrease rate of metabolism)

Eventually also compete with drug target, alter the amount of plasma protein levels etc, etc.

Question 3

Explain the impact of food on drug responses

Answer 3

• drugs may interact chemically with components of food; this may alter their absorption
• e.g. foods delay gastric emptying and alter gastric pH

Question 4

Explain the effect of fluids on drug response

Answer 4

• most drugs are better absorbed if taken with water eg may dissolve better
  
  • fluids may stimulate gastric emptying.
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Question 5

How and why do small children/newborns have a different repsonse to drugs?

Answer 5

Normally: Less metabolised/ higher action due to

• more body water than adults
• poorer renal function, with immature tubular secretion
• an immature blood brain barrier
• lower capacity for drug metabolism.

Question 6

Explain the things that might alter drug absorbtion in the elderly

Answer 6

• decreased absorptive surface of small intestine
• altered gastric and gut motility
• increased rate of gastric emptying

–> Normally: decreased absorbtion

Question 7

Explain the how drug distribution differs with increased age

Answer 7

reduced lean body mass and body water, relative increase in fat leading to

• lipid soluble drugs have increased Vd (=volume of distribution) and decreased blood levels
• water soluble drugs have decreased Volume of distribution and increased blood levels
• reduced plasma albumin, so fewer plasma protein binding sites

Question 8

Which factors influence drug metabolism in the elderly?

Answer 8

Is normally slower due to:

• splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
• liver size and hepatocyte number decrease
• hepatic enzyme activity and induction capacity decrease

Question 9

Explain the factors that influence drug dexcretion in the elderly

Answer 9

Normally slower/reduced due to:

• reduced renal mass
• reduced renal perfusion
• reduced glomerular filtration rate
• reduced tubular excretion

Question 10

How does nutritional status lead to variability in drug response?

Answer 10

• unbalanced diets may lead to deficiency states and enzyme abnormalities
• starvation – decreased plasma protein binding and metabolism
• obesity – increased lipid fraction

Question 11

How can congestive heart failure lead to altered drug responses?

Answer 11

iii) Congestive heart failure (especially in the elderly) may lead to

• reduced splanchnic blood flow
• intestinal mucosal oedema
• reduced hepatic clearance

Question 12

How can Kidney failure lead to variation in drug response?

Answer 12

• decreased drug excretion leading to toxicity
• water overload leading to changes in drug concentrations in different body fluid compartments

Question 13

How does liver disease lead to variability in response to drugs?

Answer 13

It might cause:

• reduced metabolism
• reduced first pass metabolism (hence increased bioavailability)
• decreased biliary secretion and hence decreased removal
• decreased albumin synthesis and hence reduced plasma protein binding

Question 14

What is pharmagocenetics?

Answer 14

The study of genetically determined inter-individual differences in therapeutic response to drugs ans suspectibility to adverse effects

• resticted to a single or few genes of interest
• mendelian segregation

Question 15

What is pharmacogenomics?

Answer 15

Use of genome based techniques in drug development

• not resticted to one of few genes
• use of high thoughput technologies

Question 16

How can a trait or a phenotype be regulated in the genome?

Answer 16

• monogenic
• polygenic
• polymorphic (frequent occuring momogenic variants of a grequency of >1% of the population)

Question 17

How are phenotypes in the population distributed?

Answer 17

1. Mutimodal (bi or trimodal) distribution
   
   1. determined by a single gene with polymorphic variants
2. Unomodal distribution
   
   1. indicated polygenic or multifactural
   2. or monogenic inheritance without polymorphsm

Question 18

Name an example of which phonetypes could be seen in a bi or tri-modal distribution of the phenotype drug metabolism

Answer 18

1. Enhanced/extensive metaboliser
   
   1. low plasma concentration, ususally heterozygote or homozygote dominant
2. intermediate metaboliser
3. poor metaboliser/non-metabolser
   
   1. high plasma concentration, long time
   2. homozygote recesicce

Question 19

Why is do people react differently to treatment of tuberculosis with isoniazid?

Answer 19

Because there are different polymorphisims for the ability to undertake n-acetylation reactings

• might lead to overdosing in some people with slow metabolism

Question 20

What does the Hardy-Weinberg law predict?

Answer 20

Both allele and genotype frequencies ina population remain constant (are in equilibrium) from generation unless specific disturbing factors are introduced

• Phenotyßpe: observed fast and slow metaboliser
• Genotype: Genetic makeu (FF; SS; FS; SF)
• Allele= individual copy (F or S)

Question 21

Explain the calculation of the Hardy-Weinberg-Law

Answer 21

(p+q)² = p² + 2pq + q² = 1

• =1 because it is bimodal –> have to add up to 100%
• 0.2601+0.4998+0.2401= 1
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