G4 ADME in paediatrics

Question 1

what route of administration has 100% drug availability to blood circulation?

Answer 1

intravenous injection

Question 2

what are the most frequently used routes of administration for paediatric patients?

Answer 2

extravascular routes

• GIT
• skin
• lungs

majority of drugs administered are given orally

Question 3

regarding neonates, what formulation are oral medicines usually?

Answer 3

solution based
eg. solutions or suspensions

Question 4

how may the challenge of low stability in solution or suspension be overcome?

Answer 4

by the development of sprinkles, oral dissolving films and oral disintegrating tablets

Question 5

what happens to a drug when taken orally? what does the pH partition hypothesis assume about this?

Answer 5

• drug partitions from the aqueous fluids within the GIT and the lipoidal-like membrane of the lining of the epithelium
• pH partition hypothesis assumes the GIT acts as a lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion and the GI / blood barrier is impermeable to ionised (poorly lipid soluble) forms of drugs

Question 6

what does the stomach act as when drugs are taken orally?

Answer 6

• a temporary reservoir for ingested food and dosage forms
• the stomach enables better contact of ingested material with the intestinal membrane by reducing ingested solids to a uniform semifluid known as chyme, facilitating absorption

Question 7

function of the proximal stomach with food

Answer 7

• proximal stomach (top / first part) relaxes to receive food
• gradual contractions move the food distally (towards bottom of the stomach)

Question 8

function of the distal stomach with food

Answer 8

• contractions of the distal stomach mix and break down food particles and move them towards the pyloric sphincter

Question 9

what does the pyloric sphincter allow?

Answer 9

liquids and small food particles to empty

Question 10

describe gastric retropulsion

Answer 10

• pyloric sphincter allows liquids and small food particles to empty into duodenum
• other material is retropulsed into the antrum and gets caught by the next peristaltic wave
• this happens so that larger particles are subject to further size reduction

Question 11

where might we expect weak acid drugs to be absorbed?

Answer 11

• if we disregard organ adaptations, we would expect the stomach
• actually only 30% of weak acid drugs are absorbed here
• the rest are absorbed in the small intestine due to the large surface area of the epithelium (due to villi and microvilli)

Question 12

how does the gastric pH vary in newborns?

Answer 12

• gastric pH varies in the first 24 hours of birth
• initially following birth, gastric pH is around 6-8
• subsequently drops to 2-3 within a matter of hours
• immature parietal cells which are responsible for acid secretion mean that 24 hours after birth, the pH starts to rise (because the cells in the baby that need to secrete acid are not fully developed)

Question 13

what do changes in gastric pH of neonates affect?

Answer 13

• the ionisation state of electrolyte drugs, subsequently affecting dissolution and absorption
• pH changes can also affect drug stability

Question 14

give a specific example of an acid labile drug that has absorption affected by gastric pH in neonates

Answer 14

greater peak concentrations of the acid labile drug penicillin have been observed in neonates where gastric pH is higher than that of infants and children meaning the drug is not broken down as much and so absorption is higher

Question 15

similar to penicillin, state some acid-labile microbial agents that reach higher concentrations in neonates compared to children and infants

Answer 15

ampicillin
amoxicillin
benzylpenicillin
nafcillin
flucloxacillin
erythromycin

Question 16

what is meant by acid labile?

Answer 16

breaks down in acid

Question 17

what does the relatively alkaline pH of neonates and infants’ stomachs result in? give examples of drugs affected

Answer 17

• reduced absorption of acidic drugs
• this is because they display a greater extent of ionisation and can’t be absorbed
• eg. nalidixic acid, ganciclovir, phenytoin, phenobarbital

Question 18

key determinants in the rate and extent of intestinal drug absorption

Answer 18

• gastric emptying time (rate of removal from the stomach)
• intestinal transit time

Question 19

what is generally the rate limiting step in absorption of high-solubility, high-permeability drugs?

Answer 19

gastric emptying time

Question 20

how are gastric emptying and intestinal transit time different in children to adults?

Answer 20

• GET and intestinal transit time can be variable in childhood
• reduced motility in paediatric patients means that both are typically prolonged / longer

Question 21

at what point in a child’s life does GET approach adult values? how does this affect the absorption of paracetamol?

Answer 21

• 6-8 months
• this is known to affect the absorption rate of paracetamol which is significantly lower in the first few days after birth and may not reach adult rates until 6-8 months of age

Question 22

how is Cmax different in infants? what else is observed?

Answer 22

• typically lower in preterm infants due to slow gastric emptying
• increases in Tmax are observed (delays in therapeutic effect should be considered)

Question 23

describe peristalsis in neonates

Answer 23

• irregular
• results in highly variable absorption in the small intestine

Question 24

compare intestinal transit time in young children to that in neonates and infants. what could this mean for sustained release tablets?

Answer 24

• intestinal transit time in young children appears to be shorter than in neonates / infants
• sustained release formulations may display incomplete absorption because the tablet will end up being completely excreted due to not being in the small intestine as long

Question 25

describe extrapolating data from adults for children on sustained release formulations

Answer 25

the unreliability of sustained release formulations is more marked in children than adults, extrapolation of data from adults to children is difficult

Question 26

what does immature biliary function result in?

Answer 26

- a reduced ability to solubilise lipophilic drugs - reduced ability to digest fats

Question 27

compare the luminal concentrations of bile in neonates and adults

Answer 27

- 2-4 mM in neonates (first 2 weeks) - 3-5 mM in adults

Question 28

what is bile secreted by?

Answer 28

the liver

Question 29

what is bile fluid necessary for?

Answer 29

the absorption of fats in the small intestine since is activates lipase and solubilises lipolysis products

Question 30

describe the transdermal route of administration in the paediatric population

Answer 30

- transdermal absorption may be enhanced in the paediatric population since the surface area of the skin relative to the body weight is larger than in adults - in neonates and infants, the stratum corneum and epidermis is thinner which results in a greater extent of absorption

Question 31

describe the parenteral route of administration in the paediatric population

Answer 31

in neonates, blood flow to muscle may be reduced, rendering absorption from intramuscular injections erratic and unreliable

Question 32

describe the nasal route of administration in the paediatric population

Answer 32

- the intranasal route offers times until onset of action which approach the IV route and is convenient - no changes in factors which affect absorption via this route (eg. mucus composition, pH or micociliary clearance) have been reported and so nasal formulations suitable for adults are routinely used in children

Question 33

describe the ocular route of administration in the paediatric population

Answer 33

- corneal permeation may be more rapid in neonates and infants since membranes are thinner in the eye - tear volume increases with age and diminished tear volumes in younger patients can lead to topically applied drug concentrations being higher in younger patients (eg. chloramphenicol)

Question 34

describe the pulmonary route of administration in the paediatric population

Answer 34

- small children with asthma or cystic fibrosis may require inhaled medicines - obligate nasal breathing is common at birth and in some cases up to 12 months of age meaning the route taken to the lungs can be vastly different across the paediatric population

Question 35

how can pulmonary drug devices be modified for children?

Answer 35

- modification of devices possessing mouthpieces with an infant or child size mask - no clinical evidence suggests improved response following use of one compared to the other

Question 36

developmental changes in paediatric population which affect drug distribution

Answer 36

- body composition - protein binding - cardiac output - tissue perfusion - membrane permeability

Question 37

what does the increased total body water % of the foetus and neonate result in?

Answer 37

- an increase in Vd in the case of hydrophilic drugs (eg. phenobarbital) - a decrease in Vd in the case of lipophilic drugs (eg. diazepam)

Question 38

why is binding of drugs to plasma proteins reduced in neonates?

Answer 38

- due to lower levels of albumin and altered binding capacity

Question 39

what are the total plasma protein concentrations in adults and children?

Answer 39

adult = 72 g/L child = 59 g/L

Question 40

give an example of an endogenous substance competitively binding to albumin in neonates

Answer 40

- some endogenous substances competitively bind to albumin - in neonates, high levels of bilirubin in circulation may displace drugs from the albumin binding site

Question 41

what are changes in protein binding particularly important for?

Answer 41

- drugs which are moderately to highly bound and have a narrow therapeutic index - eg. phenytoin and etoposide

Question 42

what is hyperbilirubinemia?

Answer 42

- a condition affecting neonates whereby bilirubin builds up in the blood - reduces the protein binding of ampicillin, penicillin, phenobarbital and phenytoin

Question 43

describe membrane permeability in preterm neonates

Answer 43

- membrane permeability is high - BBB is immature so penetration in to the CNS should be considered - CNS permeability subsequently decreases by the infant stages, demonstrated by a decrease in the brain / plasma ratio of anticonvulsants

Question 44

describe permability of BBB in neonates

Answer 44

more permeable

Question 45

what is the predominant enzyme family involved in gut wall metabolism of drugs?

Answer 45

- cytochrome P450 (CYPs) - CYP3A family accounts for 70% of the cytochromes present in the small intestine

Question 46

describe the CYP3A4 enzyme activity in neonates and infants, children and adults

Answer 46

neonates: - very low - increases in the first year of life - activity is greater in infants and children than in adults - medicines are frequently used in children which are metabolised by CYP3A4

Question 47

what aspects of elimination in the paediatric population will be affected by maturation? what will these affect in turn?

Answer 47

- glomerular filtration - renal tubular function both of these will affect renal clearance

Question 48

during elimination, what does unbound drug in the plasma do?

Answer 48

- passively transverses the glomerular membrane into the renal tubule

Question 49

what is glomerular filtration responsible for?

Answer 49

the elimination of a large number of water-soluble drugs and metabolites

Question 50

examples of drugs which are almost exclusively eliminated via glomerular filtration. what have these drugs been used to investigate because of this?

Answer 50

gentamicin tobramycin vancomycin because of this, these drugs have been used to investigate the age-dependence of GFR

Question 51

describe how GFR changes throughout lifespan and what we need to consider because of this

Answer 51

- reaches maturation by the age of 1 - stays virtually constant until the age of 70 therefore, all we need to consider is that children under the age of 1 may show variable elimination to drugs that are particularly water-soluble or exclusively eliminated by glomerular filtration