G4. ADME in pregnancy Flashcards
Dosage Form Considerations?
one note
The pH partition hypothesis?
The pH partition hypothesis assumes the GI tract 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
Describe stomach
The stomach acts as 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
How does the stomach work?
-Proximal stomach relaxes to receive food. Gradual contractions move the food distally.
-Contractions of the distal stomach mix and break down food particles and move them towards the pyloric sphincter.
-Pyloric sphincter allows liquids and small food particles to empty.
-Other material is retropulsed into the antrum and gets caught by the next peristaltic wave. This is so larger particles are subject to further size reduction.
ONE NOTE
Absorption in the stomach?
-Absorption of weak acid expected to be highest in the stomach according to pH partition hypothesis, but usually < 30% of dose is absorbed in stomach.
-This is mainly due to surface area differences between the stomach and small intestine
how does gastric pH values vary?
Peroral drug absorption is influenced by developmental changes in the gastrointestinal tract. Gastric pH varies within the first 24 hours of birth. Initially following birth, gastric pH is around 6 – 8, and 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 begins to rise
what are the effects of gastric pH changes?
Changes in gastric pH affect the ionisation state of electrolyte drugs, subsequently affecting dissolution and absorption. pH changes can additionally affect drug stability. For example, 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.
ONE NOTE
acid-labile microbial agents?
acid-labile microbial agents such as ampicillin, amoxycillin, benzylpenicillin, nafcillin, flucloxacillin and erythromycin reach higher concentrations in neonates in comparison to in children and adults
When is adult gastric pH value reached?
Adult gastric pH values have been reported not to be reached until the age of two, and the relatively alkaline pH before this age results in reduced absorption of acidic drugs e.g. nalidixic acid, ganciclovir, phenytoin and phenobarbital
Increased absorption?
Acid labile drugs such as anti-microbial agents
Decreased absorption
Acid drugs which display a greater extent of ionisation
gastric emptying and transmit time?
-Gastric emptying and intestinal transit time are key determinants in the rate and extent of intestinal drug absorption. Gastric emptying time (GET) represents the rate of removal from the stomach.
-In the case of high-solubility, high-permeability drugs, GET is generally the rate limiting step in absorption1.
-Gastric emptying time can be variable in childhood, as can intestinal transit time. Reduced motility in paediatric patients means that typically both are prolonged
ONE NOTE
How does gastric emptying time vary?
-GET approaches adult values in the first 6 – 8 months of life.
-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 age1.
-Cmax is typically lower in preterm infants due to slow gastric emptying and increases in Tmax are observed. Delays in therapeutic affect should be considered
peristalsis in neonates?
Peristalsis in neonates is irregular, resulting in highly variable absorption in the small intestine
the intestinal transit time in young children?
-the intestinal transit time in young children appears to be shorter. Sustained-release formulations may display incomplete absorption
-The unreliability of sustained release formulations is more marked in children than adults, and extrapolation of data from adults to children is difficult1
immature biliary function?
-Immature biliary function results in a reduced ability to solubilise lipophilic drugs2.
-Luminal concentrations of bile have been found to be 2 - 4 mM in neonates (during the first two weeks), in comparison to 3 – 5 mM observed in adults.
Biliary Function?
-Bile is secreted by the liver.
-Bile fluid is necessary for the absorption of fats in the small intestine since it activates lipase and solubilises lipolysis products.
-Immature biliary function results in reduced ability to digest fats.
transdermal drug delivery?
-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, resulting in a greater extent of absorption
parental drug delivery?
In neonates, blood flow to muscle may be reduced, rendering absorption from intramuscular injections erratic and unreliable.
nasal drug delivery?
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 i.e. mucus composition, pH, or mucociliary clearance, have been reported and so nasal formulations suitable for adults are routinely used in children.
ocular drug delivery?
Corneal permeation may be more rapid in neonates and infants since membranes are thinner in the eye in these groups. Tear volume increases with age, and diminished tear volumes in younger patients can lead to topically applied drug concentrations being higher in younger patients.
pulmonary drug delivery?
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. Modification of devices possessing mouthpieces with an infant or child size mask is common, although no clinical evidence suggest improved responses following use of one compared to the other
developmental changes which affect drug distribution?
-Developmental changes which affect drug distribution include: body composition, protein binding, cardiac output, tissue perfusion, membrane permeability.
-The increased total body water (%) of the foetus and neonates results in an increase in Vd in the case of hydrophilic drugs (e.g. phenobarbital), and a decrease in Vd in the case of lipophilic drugs (e.g. diazepam)
ONE NOTE
Drug distribution changes in neonates?
-Binding of drugs to plasma proteins in neonates is reduced due to lower levels of albumin and altered binding capacity1. Total protein concentrations: Adults = 72 g/L Neonates = 59 g/L 2.
-Some endogenous substances competitively bind to albumin. In neonates, high levels of bilirubin in circulation may displace drugs from the albumin binding site.
-Changes in protein binding are particularly important for drugs which are moderately to highly bound and have a narrow therapeutic index, for example, phenytoin and etoposide
Hyperbilirubinemia?
Hyperbilirubinemia, a condition affecting neonates whereby bilirubin builds up in the blood, reduces the protein binding of ampicillin, penicillin, phenobarbital and phenytoin (narrow therapeutic index)
membrane permeability in neonates?
Membrane permeability is high in pre-term neonates and the blood-brain barrier is immature, and so penetration into the central nervous system should be considered. CNS permeability subsequently decreases by the infant stage, demonstrated by a decrease in the brain/plasma ratio of anticonvulsants
what is cytochrome P450 (CYPs)?
The predominant enzyme family involved in gut wall metabolism of drugs is cytochrome P450 (CYPs).
CYP3A family?
CYP3A4 activity in neonates is very low, and increases in the first year of life. CYP3A4 activity is greater in infants and children than in adults, and frequently used medicines in children which are metabolised by CYP3A4.
ONE NOTE
ELIMINATION?
-Glomerular filtration will be affected by maturation, as will renal tubular function. This will affect renal clearance1.
-Unbound drug in the plasma passively transverses the glomerular membrane into the renal tubule.
-Glomerular filtration is 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?
gentamicin, tobramycin, and vancomycin. Because of this, these drugs have been used to investigate the age-dependence of GFR.
Glomerular filtration rate reaches maturation by?
the age of one, and stays virtually constant until the age of 70.
