lecture 8 - environment variability

Question 1

what is the most important quantitative determinant of drug dose and why

Answer 1

body size
- volume distribution proportional to weight

• can be used to determine loading dose by volume of distribution
• corresponding maintenance dose rates is 100 fold (due to predictable relationship between weight and CL)

Question 2

body composition

Answer 2

fat and fat-free (lean) mass

• more fat mass for women
• Fat-free mass can be predicted from weight, height, sex
• CL and V affected mainly by fat-free mass (also by fat mass)

the fraction of fat mass predicting drug elimination and distribution varies from drug to drug

Question 3

renal function

Answer 3

• differences in renal function can explain about a 10 fold difference in total drug clearance
• GFR
• always some non-renal clearance e.g. via the gut which adds 0.5L/ to renal clearance even in renal failure

Question 4

prediction of renal function

Answer 4

• serum creatinine and production in muscles (relates to muscle mass) used to calculate creatinine clearance (CLcr), which approximates glomerular filtration rate
• renal function is predicted by = predicted CLcr / normal CLcr
• also predicted by MDRD, eGFR, Schwartz methods

Question 5

hepatic function

Answer 5

difficult to predict hepatic drug CL without administrating the drug

LFTs used to measure liver damage, especially Albumin and INR changes in liver failure

Child-Pugh system stages liver failure, which is loosely correlated with hepatic CL

Question 6

age

Answer 6

post-natal age (PNA) = age since birth

post-menstrual age (PMA) = age since mothers last period
- on average 2 weeks longer than biological age

post-contraceptive age (PCA) = age since contraception

Question 7

maturation of drug clearance

Answer 7

typical maturation = 30% of adult values at full term delivery (after size scaling)

very premature babies = 10%

tramadol CL matures fast, with 50% of adult CL at birth

maturation is complete by 2 years old

CL/kg is highest at 2 years old

age in older adults has a minor influence on drug CL (once weight, renal function, etc. are
accounted for)

responsible for 10 fold difference in CL

Question 8

factors affecting drug dose

Answer 8

• body size
• renal function
• menstrual age

Question 9

Four major environmental variables contribute to inter-individual variations in drug responsiveness

Answer 9

• Body size (weight, kg)
• Body composition
• Organ function
• Maturation (of organ function)

Question 10

allometric scaling

Answer 10

• All living things are composed of cells
• Assumption: all individual cells are similar in size and have similar energy requirements
• The structure of the ‘energy delivering system’ requires a certain mass to support the delivery system, as well as the target cells
• In animals, the energy delivering system are bones and blood vessels

• The allometric scaling factor of ¾ (0.75) allows us to predict how certain physiological processes vary with body size
- e.g. metabolic rate, clearance

Question 11

when is maturation complete

Answer 11

organ maturation in relation to clearance is complete by 2 years of age

Question 12

what component of body weight is important in clearance

Answer 12

Blood volume - influenced by degree of vascularization and tissue volume