Donna M. Kraus, Pharm.D.
Spring 1998
Donna M. Kraus, Pharm.D.
Spring 1998
Pediatric Case: Developmental Pharmacotherapeutics
The year is 2001, and you are a pharmacist working the midnight shift at Sick Baby Hospital in Mightytown, USA. You receive a phone call from a first year M.D. intern about the following patient:
RH is a 6 day male infant born at full term (weight 4.5 Kg) with a diagnosis of R/O sepsis. The patient is currently receiving Ampicillin and Gentamicin at the appropriate doses. The blood culture results are positive for E. Coli which is sensitive to: amikacin, ampicillin, gentamicin, ceftriaxone, ceftazidime, and itokazumycin (pronounced it-o-kat-zu-my-cin)
The intern asks about the use of itokazumycin in this newborn patient. He's heard about the drug and its use in adults and wants to know if he could use it in this patient. Since you keep up with all the new drugs, you know the following information about itokazumycin:
* The drug is acid labile
* It is metabolized via the P-450 enzyme system by hydroxylation and by glucuronide synthesis
* In very high (toxic) doses in animals, vascular collapse has been seen
* The drug comes both in po and iv preparations
* The IV preparation contains benzyl alcohol
* There are no published studies in newborns, neonates, infants, or children.
1. Comment on the possible expected oral absorption of itokazumycin in this patient.
2. Would the probable expected maintenance doses (per kg) of the drug be higher or lower compared to an adult and why?
3. Describe 2 potential problems which may occur if this drug were given IV to this newborn. List what you think would be the probable mechanisms (i.e., talk about metabolic pathways).
KEY
The year is 2001, and you are a pharmacist working the midnight shift at Sick Baby Hospital in Mightytown, USA. You receive a phone call from a first year M.D. intern about the following patient:
RH is a 6 day male infant born at full term (weight 4.5 Kg) with a diagnosis of R/O sepsis. The patient is currently receiving Ampicillin and Gentamicin at the appropriate doses. The blood culture results are positive for E. Coli which is sensitive to: amikacin, ampicillin, gentamicin, ceftriaxone, ceftazidime, and itokazumycin (pronounced it-o-kat-zu-my-cin)
The intern asks about the use of itokazumycin in this newborn patient. He's heard about the drug and its use in adults and wants to know if he could use it in this patient. Since you keep up with all the new drugs, you know the following information about itokazumycin:
* The drug is acid labile
* It is metabolized via the P-450 enzyme system by hydroxylation and by glucuronide synthesis
* In very high (toxic) doses in animals, vascular collapse has been seen
* The drug comes both in po and iv preparations
* The IV preparation contains benzyl alcohol
* There are no published studies in newborns, neonates, infants, or children.
1. Comment on the possible expected oral absorption of itokazumycin in this patient.
Since this newborn would have a relative achlorhydria, there would be an expected increase in the bioavailability of any acid labile drug. Remember from the lecture:
At birth gastric pH ranges from 6 - 8 due to residual amniotic fluid in the stomach. (Amniotic fluid is regularly swallowed during intrauterine life.) Gastric pH then falls to a pH of 1.5 to 3 within 24 to 48 hours after birth but during the first week of life returns to neutrality. Gastric pH then decreases gradually to adult values after approximately 2 years of age (range 3-7 yrs). This higher pH which normally occurs during this time is referred to as a "relative achlorhydria".
This relative achlorhydria can result in an increased bioavailability of acid labile drugs such as penicillin, nafcillin, and ampicillin and a decreased absorption of acidic drugs such as phenobarbital, phenytoin, and nalidixic acid. (Remember that a weakly acidic drug in a relatively alkaline environment will result an increase in the ionized form of the drug which would result in decreased absorption.)
* NOTE: Students may also add the following information about gastric emptying time or peristalsis as listed below, but I was just mainly looking for the above information related to possible increase in bioavailability.
Gastric emptying time in neonates and premature infants is prolonged (up to 6-8 hours) with adult values being reached at 6-8 months of age. Gastric emptying time is dependent upon gestational age, postnatal age, and type of feeding. The prolonged gastric emptying time seen in neonates and young infants results in delayed drug absorption. A delay in the time to peak as well as a decrease in the peak concentration of several drugs may be seen.
Peristalsis in the newborn can be irregular and unpredictable. This may result in a prolonged contact time with the G.I. mucosa and possibly an increase in drug absorption.
2. Would the probable expected maintenance doses (per kg) of the drug be higher or lower compared to an adult and why?
One would expect that the maintenance doses would be lower in this patient compared to adults. This would be due to the lower rates of metabolism seen in newborns for the P-450 hydroxylation and the glucuronide synthesis pathways.
From lecture remember that:
Newborns have decreased activity of many enzyme pathways. Typically, if a drug's primary metabolic pathway is decreased, clearance of the drug is decreased and daily maintenance doses must be decreased or accumulation of the drug will result. This explains the decreased mg/kg/day doses which are required for many drugs in neonates.
* NOTE: You may ask yourself, so what metabolic pathways are decreased at birth?
Esterase (hydrolysis) activity is decreased in newborns and increases gradually over first year of life. Example: decreased hydrolysis of procaine ester anesthetics.
Hepatic microsomal activity (oxidative reactions) is also decreased in neonates.
In vitro evaluation of enzyme activity has demonstrated that for a term infant: Cytochrome P-450 and NADPH-Cytochrome C-Reductase Activity are approximately 1/2 that of adult values. (range: 20-70%)
Newborns have decreased hydroxylation activity which results in decreased metabolism of phenobarbital, phenytoin, lidocaine, amobarbital and diazepam.
Newborns have decreased N-demethylation activity (Dealkylation) which results in the decreased metabolism of theophylline, meperidine and diazepam.
Glucuronide Synthesis (Microsomal) is decreased in the newborn and reaches adult levels by 3 years of age. Due to decreased activity of UDPG - glucuronyl transferase, a decrease in the metabolism of bilirubin, morphine, and chloramphenicol is observed in neonates.
3. Describe 2 potential problems which may occur if this drug were given IV to this newborn. List what you think would be the probable mechanisms (i.e., talk about metabolic pathways).
1. Vascular collapse due to accumulation of the drug. (perhaps a "gray baby syndrome" like that which occurs with chloramphenicol). Since the normal metabolic pathways of this new drug (hydroxylation and glucuronide synthesis) are decreased in the newborn/neonate, if the drug were given in mg/kg doses comparable to adults, (or in too high of doses for the metabolic rate) the drug could accumulate and cause the toxic reaction which was reported in animals (i.e. vascular collapse).
2. Benzyl alcohol gasping syndrome may occur due to a decrease in glycine conjugation seen in neonates and accumulation of benzoic acid.
Remember from class: Glycine conjugation is decreased in neonates and reaches adult levels at approximately 8 weeks of age. Because of decreased glycine conjugation, benzoic acid can accumulate in newborns given excess benzyl alcohol or benzoic acid.
Benzyl alcohol--> benzoic acid ----> glycine conjugation-----> hippuric acid.
This accumulation of benzoic acid results in the "benzyl alcohol gasping syndrome" with deterioration of multiple organ systems, severe metabolic acidosis and gasping respirations. This is a dose related syndrome and has been reported with doses of benzyl alcohol greater than 99 mg/kg. Because of this syndrome, the FDA now recommends that drugs containing benzyl alcohol or benzoic acid as preservatives should NOT be used in neonatal nurseries.
Therefore, one should USE PRESERVATIVE FREE MEDICATIONS FOR NEONATES
(and especially for premature newborns)
**** Now ask yourself, would you really want to use itokazumycin in this patient?
Answer: No way, No how!! Risks are too great, especially since the drug does not look like it offers any distinct advantage over currently available medications. The bug (E. Coli.) is sensitive to available antibiotics which have been studied and used in this population. Also, the correct dose would not be known.
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