G4 ADME in paediatrics Flashcards
what route of administration has 100% drug availability to blood circulation?
intravenous injection
what are the most frequently used routes of administration for paediatric patients?
extravascular routes
- GIT
- skin
- lungs
majority of drugs administered are given orally
regarding neonates, what formulation are oral medicines usually?
solution based
eg. solutions or suspensions
how may the challenge of low stability in solution or suspension be overcome?
by the development of sprinkles, oral dissolving films and oral disintegrating tablets
what happens to a drug when taken orally? what does the pH partition hypothesis assume about this?
- 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
what does the stomach act as when drugs are taken orally?
- 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
function of the proximal stomach with food
- proximal stomach (top / first part) relaxes to receive food
- gradual contractions move the food distally (towards bottom of the stomach)
function of the distal stomach with food
- contractions of the distal stomach mix and break down food particles and move them towards the pyloric sphincter
what does the pyloric sphincter allow?
liquids and small food particles to empty
describe gastric retropulsion
- 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
where might we expect weak acid drugs to be absorbed?
- 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)
how does the gastric pH vary in newborns?
- 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)
what do changes in gastric pH of neonates affect?
- the ionisation state of electrolyte drugs, subsequently affecting dissolution and absorption
- pH changes can also affect drug stability
give a specific example of an acid labile drug that has absorption affected by gastric pH in neonates
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
similar to penicillin, state some acid-labile microbial agents that reach higher concentrations in neonates compared to children and infants
ampicillin
amoxicillin
benzylpenicillin
nafcillin
flucloxacillin
erythromycin
what is meant by acid labile?
breaks down in acid
what does the relatively alkaline pH of neonates and infants’ stomachs result in? give examples of drugs affected
- 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
key determinants in the rate and extent of intestinal drug absorption
- gastric emptying time (rate of removal from the stomach)
- intestinal transit time
what is generally the rate limiting step in absorption of high-solubility, high-permeability drugs?
gastric emptying time
how are gastric emptying and intestinal transit time different in children to adults?
- GET and intestinal transit time can be variable in childhood
- reduced motility in paediatric patients means that both are typically prolonged / longer
at what point in a child’s life does GET approach adult values? how does this affect the absorption of paracetamol?
- 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
how is Cmax different in infants? what else is observed?
- typically lower in preterm infants due to slow gastric emptying
- increases in Tmax are observed (delays in therapeutic effect should be considered)
describe peristalsis in neonates
- irregular
- results in highly variable absorption in the small intestine
compare intestinal transit time in young children to that in neonates and infants. what could this mean for sustained release tablets?
- 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
describe extrapolating data from adults for children on sustained release formulations
the unreliability of sustained release formulations is more marked in children than adults, extrapolation of data from adults to children is difficult
what does immature biliary function result in?
- a reduced ability to solubilise lipophilic drugs
- reduced ability to digest fats
compare the luminal concentrations of bile in neonates and adults
- 2-4 mM in neonates (first 2 weeks)
- 3-5 mM in adults
what is bile secreted by?
the liver
what is bile fluid necessary for?
the absorption of fats in the small intestine since is activates lipase and solubilises lipolysis products
describe the transdermal route of administration in the paediatric population
- 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
describe the parenteral route of administration in the paediatric population
in neonates, blood flow to muscle may be reduced, rendering absorption from intramuscular injections erratic and unreliable
describe the nasal route of administration in the paediatric population
- 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
describe the ocular route of administration in the paediatric population
- 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)
describe the pulmonary route of administration in the paediatric population
- 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
how can pulmonary drug devices be modified for children?
- 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
developmental changes in paediatric population which affect drug distribution
- body composition
- protein binding
- cardiac output
- tissue perfusion
- membrane permeability
what does the increased total body water % of the foetus and neonate result in?
- an increase in Vd in the case of hydrophilic drugs (eg. phenobarbital)
- a decrease in Vd in the case of lipophilic drugs (eg. diazepam)
why is binding of drugs to plasma proteins reduced in neonates?
- due to lower levels of albumin and altered binding capacity
what are the total plasma protein concentrations in adults and children?
adult = 72 g/L
child = 59 g/L
give an example of an endogenous substance competitively binding to albumin in neonates
- some endogenous substances competitively bind to albumin
- in neonates, high levels of bilirubin in circulation may displace drugs from the albumin binding site
what are changes in protein binding particularly important for?
- drugs which are moderately to highly bound and have a narrow therapeutic index
- eg. phenytoin and etoposide
what is hyperbilirubinemia?
- a condition affecting neonates whereby bilirubin builds up in the blood
- reduces the protein binding of ampicillin, penicillin, phenobarbital and phenytoin
describe membrane permeability in preterm neonates
- 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
describe permability of BBB in neonates
more permeable
what is the predominant enzyme family involved in gut wall metabolism of drugs?
- cytochrome P450 (CYPs)
- CYP3A family accounts for 70% of the cytochromes present in the small intestine
describe the CYP3A4 enzyme activity in neonates and infants, children and adults
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
what aspects of elimination in the paediatric population will be affected by maturation? what will these affect in turn?
- glomerular filtration
- renal tubular function
both of these will affect renal clearance
during elimination, what does unbound drug in the plasma do?
- passively transverses the glomerular membrane into the renal tubule
what is glomerular filtration responsible for?
the elimination of a large number of water-soluble drugs and metabolites
examples of drugs which are almost exclusively eliminated via glomerular filtration. what have these drugs been used to investigate because of this?
gentamicin
tobramycin
vancomycin
because of this, these drugs have been used to investigate the age-dependence of GFR
describe how GFR changes throughout lifespan and what we need to consider because of this
- 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
