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Flashcards in Environmental Variability Deck (14):

What is the major source of variability affecting patient response to medicines? Explain the fold increase required in dosing.

Body size.

Human body size can range from 500g to 250kg. This is a 500 fold increase in weight and be directly/linearly translatable into drug loading dose differences. (for paracetemol a 250kg person would require 500x the dose a 500g baby would require).


What is the relationship between weight and maintenance does?

However because of the relationship between maintenance dose and clearance the difference in maintenance dose rates would only be about 100 fold.


What is allometry?

The study of the relationship between body size to body shape.


Why is there not a linear increase in clearance with weight?

This is due to allometry of humans. The strucutre of the bodies energy delivery system to cells (the blood vessels) requires a certain mass to support it. A 250kg person may have really big heavy bones to support them but these dont really contribute to the clearance of the drug. (a lot of our body weight isnt directly contributing - it is just there for support).


Describe how we can assume a 2 year old to just be a small adult.

By 2 years old the body is 'mature' in the sense that it is developed enough to have the same ability for drug clearance. Therefore the equation:
CL child = CL dult x (WT child / WT adult) ^3/4

So by simply comparing the weight of the child to an adults weight and clearance and allometric scaling factor we can predict their clearance.


What is the allometric scaling factor and how was it found?


It is the slope of the graph between weight and allometric size.


Althought the allometric theory dosent take into account body composition (fat free mass and fat mass), what is drug clearance mainly driven by?

Fat free mass.

Fat dosent metabolize drugs - it dosent have any CYP enzymes.

There is a pretty easy way to determine this by just knowing their age, gender, height etc. Men generally have 22% fat and women 28% mass. The fraction of drug being distributed and cleared by fat mass varies between drugs.


What fold increase in total drug clearance can be attributed to renal function?

10 fold increase (from those that have renal failure to those with normal kidneys).

(GFR is 7L/h in healthy adult, 0.5L/h in kidney failure)
In kidney failure patients there is some non renal clearance that allows for some drug clearance.

Renal function is predicted by creatinine clearance.


How is liver function measured in terms of drug clearance?

It is very hard to determine hepatic clearance without actually administering the drug.

Often it is estimated from liver function tests (measure AST and ALT from blood tests). However this dosen't directly relate to drug metabolism.


What is the best way to describe the age of a baby when predicting drug metabolism?

Post menstrual age (how old it is since the mothers last menstrual period).

This predicts the maximum age a baby can be. Generally the baby will be conceived two weeks after the last menstrual period as there is when fertilisation occurs.

This is a good measure as we predict how mature the baby is.


At full term delivery, babies maturation is 30% of adult values. what does this mean?

It has renal and hepatic function that is 30% of that of an adult. By 2 years these can be assumed to be 100% of an adults (body size scaled/accounted for).

Maturation is complete by 2 years old. Then it is weight that is the sole predictive factor for drug clearance.

Note: during maturation, different enzymes mature at diffrerent rates. Tramadol matured very fast.


When is clearance per kg highest in life?

2 years old

HIghest dose required at this age.

At this point maturation and size mean clearance is at a peak.


Does clearance decrease with ageing?

Not really once weight (loss of muscle mass) and renal function are accounted for.

Once enzymes have reached maturity at 2 years old we keep replacing them every 2 weeks


So in conclusion, what are the relative impacts of body size, renal function, post menstrual age on drug dose?

Body size - 100 fold difference in clearance
Renal function - 10 fold diff
PMA - 10 fold diff

Genetic factors also contribute but hardly anything (2.5% approx).