L9. Internal Environmental Variability

Question 1

What are the major sources of variability affecting the response to medicines

Answer 1

1. Body size
2. Age/ Renal function or maturation
3. Body composition
4. Body water content
5. Hepatic function

Question 2

How does body size (up to 500 fold range) affect variability of drug dose

Answer 2

• It is directly proportional to the volume of distribution, and therefore leads to differences in loading dose.
• The allometric prediction of relationship between metabolic rate (clearance) and weight is not 1:1 so the range of maintenance dose is only 100 fold range.

Question 3

What assumptions does the allometric prediction of the relationship between clearance rate and weight have

Answer 3

• all cells are similar in size and have similar energy requirements
• the structure of the energy delivery system (cvs) requires certain mass and this mass overhead can increase the total body mass without a linear increase in function (metabolic rate/clearance)
• therefore the slope is 3/4- not Linear

Question 4

What does Post natal age, post menstrual age and post conception age mean and which one is used to calculate drug dosing?

Answer 4

PNA: the age from birth; does not account for in-utero maturation
PMA; on average 2 weeks longer than biological age- time from first day of last period to birth (+ pna)
- Most reliable for drug dosing for premies
PCA: true biological age- not widely recorded.

Question 5

How does ageing or Maturation affect drug clearance/ metabolism

(In adults old age is a minor influence on drug clearance once weight and renal function is accounted for (~25%))

Answer 5

Maturation of kidneys will give 10 fold increase in glomerular filtration rate from 24 weeks pma- 1 yr pna - with completion by 2 yrs of age. Full term baby has 50% of adult renal function

After which weight is the sole predictive factor for drug clearance.

Shown as a sharp increase then plateau - still need % of adult dose until >15 yo.

Question 6

How does Body composition: fat mass: fat free mass (predicted from total body weight, height, sex- women more)
affect clearance/ metabolic rate

Answer 6

-Drug clearance and volume of distribution is driven mainly by fat free mass (but also by fat mass).
The fraction of fat mass predicting drug elimination and distribution varies for the drug. This fraction is multiplied by the fat mass to find the equivalent fat free mass determining either Cl or Vd. The resulting sum of equivalent + fat free mass = normal fat mass, which is used in allometric scaling to combine body mass and composition

Question 7

How does Growth affect clearance/ metabolic rate

Answer 7

Organ size increase and organ blood flow changes over lifetime and the rates differ between different organs.

Question 8

How does Body water content affect clearance/ metabolism

Answer 8

Drugs differ on water solubility. more water soluble drugs will have higher volume of distribution in the body if there is higher total body water which is greatest when you are a baby

Question 9

How does Renal function affect clearance/ metabolism

Answer 9

Differences in renal function can explain about 10 fold difference in total drug clearance as Kidney excretes the products of metabolism. (7L/hr (healthy) to 0.5L/hr: dialysis)
Related to weight and age- renal maturation.
Predicted by Serum creatinine clearance (GFR). Renal function is calculated relative to normal CLcr for weight and age.

Question 10

How does Hepatic function affect clearance and metabolism

Answer 10

Difficult to predict hepatic drug clearance without administering the drug.
Liver function tests measure liver damage but not function.