Variability due to Environmental differences Flashcards
What is the most important determinant of drug dose?
Body weight.
the more than 500 fold range in size across humans is directly linked to the volume distribution, and thus loading doses differ. (e.g a sumo wrestler will need 500x more paracetamol than premature baby)
What is different about clearance?
Due to allometric relationships, the relationship between and body weight and clearance, the range of maintenance dose rates is only different by 100 fold for these massive body weight differences. (500g to 250kg)
What is the theoretical foundation for allometric scaling?
All cells need are of similar size and require energy requirements. As someone gets larger, there delivery and structural systems need more enrgy, so not all the food is getting to target cells. This gives an allometric scale factor of about 3/4.
So clearance of a child can be linked by clearance of an adult times the weight of child/ weight of adult ^ 3/4
What does this allometric size show when plotted against clearance?
Clearance will increase as you increase weight, but due to the scaling factor, the clearance rate and thus maintenance dose rate will differ by 100 fold between a 0.5 kg person vs 250kg person
What can be said about body composition?
Can talk about fat mass (22% M, 28% F) and fat free mass (determined from weight, sex and height)
Drug clearance and volume distribution is driven by the fat free mass but also by fat mass
What can be said about renal function and how it varies?
Differences in renal function can explain a 10 fold difference in clearance
Serum creatinine is used to predict creatinine clearance, and is similar to GFR. Renal function is predicted/ normal clearance
What can be said about hepatic function?
It is difficult to predict this without administering the drug itself.
Can order LFT’s but not very good, eg viral hepatitis shows very high AST and ALT but clearance isn’t impaired
How old is a baby and what age is usually used?
PNA- post natal
PMA- post menstrual (after last period) we use this, longer than the PCA
PCA- post conception, the ‘biological age’
Maturation and ageing of drug clearance
Maturation: at full term delivery, a baby will have 30% of the clearance of an adult (metabolic mainly?). There is 10 fold increase of GFR from 24 PMA to 1 year PNA
Ageing: As we get older our metabolic function of clearance barely goes down
What does the clearance maturation graph show?
That maturation is complete by about 2 years of age (PMA?) exception is for tramadol, and the enzyme is very active during gestation
Why does a young child need a higher dose (in mg/kg)? (explained by age and weight)
If we take clearance using postnatal age, and divide by the predicted weight at that ages, the clearance per kilogram is at its highest when very young. (due to maturation increasing the rate of clearance, obv as you get older clearance does increase)
so clearance is still lower in children, so you give a lower dose, but the dose in mg/kg is higher.
How can you use PNA and PMA?
Use these values along with typical weights in a table show the fraction of the adult dose you would give
