Prescribing Drugs in Neonates, Infants, Children and Adolescents

Question 1:
Starting in which year are drug manufacturers required to prove both effectiveness and safety of a drug to the FDA before marketing?

1. 1938
2. 1962
3. 1966
4. 1983

Question 2:
All drugs are tested in infants and children before approval.

True or False?

Question 3:
Body composition changes during development, and premature babies contain over 80% water.

True or False?

Question 4:
Glomerular filtration rate (GFR), a measure of the power of kidneys to clear medication, increases considerably in the first two weeks of life.

True or False?

Question 5:
Pharmacogenetic differences in drug metabolizing enzymes can affect how an individual baby responds to medications.

True or False?

Question 6:
The levels of drug-metabolizing enzymes change during development before and after birth.  The levels of some of these enzymes increase, some decrease, and others are not affected.

True or False?

Question 7:
A single dose of propofol, a sedative and anesthetic, in premature infants less than 10 days old can stay in the body for hours to days, much longer than in full-term infants.

True or False?

Case Study 1
A newborn female preterm infant with a gestational age of 26 weeks and a birth weight of 850 grams was delivered by cesarean section. She was admitted to the neonatal intensive care unit (NICU) because of respiratory insufficiency and was treated with ampicillin and gentamicin because of suspicion of a severe bacterial infection.

1. What is currently the dose of gentamicin that will be prescribed to this preterm infant?
A. 2.5 mg/kg three times a day
B. 2.5 mg/kg twice a day
C. 2.5 mg/kg once a day
D. 4-5 mg/kg once every 36 hrs

After the infant is treated for 48 hrs with these broad spectrum antibiotics, her blood cultures do not show any bacterial growth, and the attending neonatologist decides to discontinue the antibacterial treatment.

Three weeks later, this little infant develops unstable temperature, decreased tolerance of oral feedings and increased episodes of apnea/bradycardia and is again suspected of having a several bacterial infection. After obtaining cultures, the attending neonatologist decides to start broad spectrum antibiotics including again gentamicin.

2. This time, the clearance and volume of distribution of gentamicin will be different from the clearance and volume of distribution of gentamicin during the first treatment of this young infant. What do you expect to happen?
A. Clearance will be more and volume of distribution will be larger
B. Clearance will be less and volume of distribution will be larger
C. Clearance will be more and volume of distribution will be smaller
D. Clearance will be less and volume of distribution will be smaller

Several weeks later, she develops severe gastro-esophageal reflux and the attending neonatologist decides to prescribe a proton pump inhibitor. At that time, it is known that she has the following genotype of CYP2C19: *1/*17. As a consequence, she will metabolize CYP2C19 substrates faster than individuals with a wild type genotype (*1/*1).

3. Which statement about proton pump inhibitors is correct?
A. All proton pump inhibitors have the same dependency
B. All proton pump inhibitors are not influenced by CYP2C19
C. Omeprazole is more dependent on CYP2C19 than Pantoprazole
D. Pantoprazole is more dependent on CYP2C19 than Omeprazole

Case Study 2
A fullterm newborn male infant is delivered urgently by caesarean section because of signs of perinatal asphyxia. After delivery, he is admitted to the NICU for further evaluation and treatment. Clinical and laboratory evaluations indicate impaired renal function due to this perinatal asphyxia. The attending neonatologist wants to prescribe antibacterial treatment and needs help to decide whether and how to adjust the dose of gentamcin in this infant.

1. What would be the best advice?
A. No need to adjust dosing of antibacterial agents in this infant
B. Same dose can be used but dosing frequency needs to be increased
C. Same dose can be used but dosing frequency needs to be decreased
D. A higher dose needs to be used but no need to change the dosing frequency

1. What is currently the dose of gentamicin that will be prescribed to this preterm infant?

Answer: D
Preterm infants have a large volume of distribution for drugs that are distributed into the extracellular water compartment. For that reason, the dose needed to reach an appropriate peak concentration is higher than in older newborns. However, preterm infants have an impaired renal function. Therefore, they need more time to clear the drug from their system. Therefore, 4-5 mg/kg is indicated to reach an appropriate peak concentration, but a prolonged (36 hrs) time is needed to clear the drug from this neonate’s body.

2. This time, the clearance and volume of distribution of gentamicin will be different from the clearance and volume of distribution of gentamicin during the first treatment of this young infant. What do you expect to happen?

Answer: C
Postnatal maturation results in an increased clearing capacity as well as a decrease in the extracellular water compartment. As a result, the clearance of gentamicin will increase, but the volume of distribution will become smaller.

3. Which statement about proton pump inhibitors is correct?

Answer: D
Proton pump inhibitors are dependent on different enzymes for their metabolism. In this case, pantoprazole is much more dependent on CYP2C19 than omeprazole. Therefore, the *17 genetic variant in CYP2C19 will be much more important for a different clearance of pantoprazole than of omeprazole because the latter is dependent equally on CYP2C19 and CYP3A4.

Case Study 2

What would be the best advice on dose adjustment?

Answer: C
Perinatal asphyxia might result in multiple organ dysfunction. In this case, renal function has been diminished due to the asphyxia. As a consequence, the clearing capacity of this newborn infant is impaired and therefore the dosing interval needs to be prolonged (frequency needs to be decreased) to assure no accumulation of gentamicin. The dose to reach efficacy does not need any adjustment.

Question 1:
Starting in which year are drug manufacturers required to prove both effectiveness and safety of a drug to the FDA before marketing?

1938
1962
1966
1983

Answer: B
In 1962, the Kefauver-Harris amendments to the Food, Drug and Cosmetics Act required drug manufacturers to prove the effectiveness as well as the safety of a drug to the FDA before marketing.  In addition, adverse effects must be reported to the FDA.

Question 2:
All drugs are tested in infants and children before approval.

True or False?

Answer: False
Drugs are often not tested in children or infants before approval.

Question 3:
Body composition changes during development, and premature babies contain over 80% water.

True or False?

Answer: True
Premature babies consist of about 60% extracellular water and over 20% intracellular water.  The proportion of water decreases during growth and development.  As a result, the dosing of medications that are dispersed in extracellular water can be significantly different for patients at different stages of development: premature babies, infants, children, and adults.

Question 4:
Glomerular filtration rate (GFR), a measure of the power of kidneys to clear medication, increases considerably in the first two weeks of life.

True or False?

Answer: True
Glomerular filtration rate (GFR), and medication clearance increase rapidly with age in newborn babies.  As a result, babies a few days old are more prone to overdosing in the NICU than children a few weeks old.

Question 5:
Pharmacogenetic differences in drug metabolizing enzymes can affect how an individual baby responds to medications.

True or False?

Answer: True
Pharmacogenetics plays an important role in drug metabolism and therefore in the selection of appropriate doses for drugs.  For example, the number of inherited functional genes (alleles) of CYP2C19 determines how Omeprazole (a proton pump inhibitor) is metabolized and whether the drug is able to effectively increase intragastric pH.

Question 6:
The levels of drug-metabolizing enzymes change during development before and after birth. The levels of some of these enzymes increase, some decrease, and others are not affected.

True or False?

Answer: True
Three different classes of drug-metabolizing enzymes (Classes 1, 2, and 3) are affected differently by development.  For example, CYP3A7 (Class 1) activity is high before birth and decreases after birth, and CYP3A4 (Class 3) activity is very low before birth and increases after birth.  The activity of SULT1A1 (Class 2) does not change significantly before and after birth.

Question 7:
A single dose of propofol, a sedative and anesthetic, in premature infants less than 10 days old can stay in the body for hours to days, much longer than in full-term infants.

True or False?

Answer: True
Premature infants less than 10 days old clear propofol more slowly than when they are over 10 days old, and they also clear the drug more slowly than full-term infants of the same age.