a) Infants have a larger extracellular fluid compartment and greater TBW content.

b) There is a greater adipose content and a higher ratio of water to lipid. Fat content is approximately 12% at birth, doubling by 6 months of age and reaching 30% at 12 months of age.

c) These factors lower plasma drug concentrations when water-soluble drugs are administered according to weight.

d) A larger drug loading dose is required to achieve the desired plasma concentration. The effect of immaturity on the volume of distribution is not as evident for lipophilic drugs that are transported across cell membranes.

a) Total plasma protein is decreased in infants, reaching equivalent adult concentrations by childhood.

b) Both albumin and alpha 1-acid glycoprotein (AAG) concentrations are diminished at birth but reach the adult equivalency by infancy (age 4 weeks).

a) Phase II reactions, which are immature at birth, consist of conjugation or synthesis. Conjugation couples the drug with an endogenous substrate (glucuronidation, methylation, acetylation, and sulfation) to facilitate excretion.

b) Newborns lack the capacity to efficiently conjugate bilirubin (decreased glucuronyl transferase activity), and metabolize acetaminophen, chloramphenicol, and sulfonamides.

c) Although the necessary enzyme systems are present at birth, enzyme activity is reduced, increasing drug elimination half-lives.

a) Drugs are usually formulated as liquids for oral administration in children.

b) Midazolam may be administered orally for premedication, and the rectal route may be selected for the administration of acetaminophen, opioids, barbiturates, and benzodiazepines.

c) Both routes rely on passive diffusion for drug absorption. The resulting plasma drug concentration depends on the molecular weight, degree of drug ionization, and lipid solubility.

d) Orally administered drugs are generally reserved for older children because gastric pH is elevated in neonates at birth (pH 6 to 8), and although decreased to a pH level of 1 to 3 within 24 hours, adult gastric pH values are not consistent until age 2 years.

e) Gastric absorption is reduced after oral administration of acidic drugs in infants. Gastric emptying time reaches adult values by 6 months of age. Although gastric emptying time does not affect drug absorption, it may alter peak drug concentration.

f) Acetaminophen, a metabolite of phenacetin, is a popular and safe analgesic and antipyretic commonly administered to children during the perioperative period.

g) The analgesic and antipyretic effects of acetaminophen are equivalent to those of aspirin when the drugs are administered in equipotent dosages.

h) Suppositories should not be divided in an attempt to provide the exact calculated dose because the suspended acetaminophen is distributed unevenly within the suppository. Recommended acetaminophen doses have been based on the age of the child, weight, body surface area calculations, and fractions of adult dosages.

i) Currently recommended oral and rectal doses of acetaminophen range from 10 to 15 mg/kg every 4 hours. Because of the variable absorption of acetaminophen suppositories, some practitioners have advocated the administration of larger initial rectal dosages. It should be emphasized that subsequent rectal doses should be decreased (20 mg/kg), and the dosing interval should be extended to every 6 to 8 hours.

j) After acetaminophen administered during the perioperative period, the parents should be informed as to the time of administration and be advised of appropriate acetaminophen dosages (60-65 mg/kg/day).

k) The daily acetaminophen dosage administered either rectally or orally should be limited to 100 mg/kg/day for children and 75 mg/kg/day for infants.

l) Sedation with nasally administered midazolam (0.2 mg/kg) may be achieved in as little as 10 to 20 minutes and is explained in part through drug absorption via the olfactory mucosa. Nasal administration is unpleasant because midazolam produces a burning of the nasal mucosa.

m) Oral fentanyl, although effective in producing significant sedation, has been plagued by significant side effects, including facial pruritus (up to 80%) and postoperative nausea and vomiting, seven times greater than when a child receives an oral meperidine, midazolam, or atropine premedicant.

n) Water-soluble drugs (atropine, fentanyl, lidocaine, morphine) may be administered via inhalation; however, only 5% to 10% of the administered dose will reach the systemic circulation.