1. Neonatal and Pediatric Pharmacotherapy

2. Learning Objectives
Be able to define and understand common developmental terms.
Explain developmental factors that affect the absorption, distribution, metabolism, and elimination of drugs.
Give examples of common drugs that are affected during postnatal development.
Apply practical concepts in neonatal and pediatric pharmacotherapy to optimize medication safety.
Be familiar with common neonatal and pediatric drug resources and their contents.

3. KIDS AND BABIES?!?!

4. Pediatric Stages of Development
Neonate
Birth- 1 month
Infant
1 month to 1 year of age
Child
1 to 12 years of age
Adolescent
12 to 18 years of age

5. Common Neonatal Terms Term infant
38-42 weeks of gestational age at birth
Preterm infant (preemie)
< 37 weeks gestational age at birth
Low birth weight infant
< 2.5kg at birth
Very low birth weight
< 1.5kg at birth
Extremely low birth weight
< 1kg at birth

6. Common Neonatal Terms Gestational Age Postnatal Age
Estimation in weeks of time from conception to birth
Postnatal Age
Chronological age after birth
Postconceptional Age
Gestational age + postnatal age
Useful in preterm babies

7. Example of Calculating Age
A child was born at 30 weeks gestational age on 7/24/08
What is the child’s postconceptional age today (8/14/08)?
30 weeks plus 21 days is 33 weeks

8. Physiologic Changes During Development

9. Pharmacokinetic Parameters Absorption Distribution Metabolism Elimination

10. Drug Absorption Bioavailability Solubility Oral absorption
Water vs. lipid
Oral absorption
Relies on functional capacity of GI tract
Percutaneous absorption
↑ in neonates and infants (3x)
Intramuscular absorption
Erratic due to differences in muscle mass
1)Fraction of drug that reaches systemic circulation 2)Lipid and water-solubility of drug 3)Most drugs given by oral route are absorbed by passive diffusion into the small intestine. Oral absorption is typically adequate in infants and small children and not greatly affected by maturational changes 4)IM absorption relies on drug to be water-soluble at physiologic pH and depends on blood flow, surface area, and penetration of drug What drugs do we routinely give IM to pediatric patients? -Immunizations, ceftriaxone, penicillin G benzathine (long-acting)

11. GI System of the Neonate
Prolonged gastric emptying time
↓ gastric acid secretion
↓ pancreatic enzyme activity
↓ biliary activity
Developing composition of intestinal microflora
1)Rate of gastric emptying is dependent on organ maturity at birth, postnatal age and composition of feedings - 6 months to reach adult values - Peristalsis is absent during first 2-4 days of life 2) gastric acid secretion develops independent of birth wgt and gestational age -neonate=relative achlorhydria=inc. BA following oral basic drugs (pcn) -Acid output ­ in proportion to body wgt. 3) What are the pancreatic enzymes? -Anaerobic bacteria present by 4-6 days after birth (full-term, formula-fed) -GI colonization depends more on diet than age

12. Drug Absorption Neonate Infant Child Adult Gastric emptying Irregular
Neonate
Infant
Child
Adult
Gastric emptying
Irregular
Increased
slightly increased
normal
Gastric pH
6-8
2-4
2-3
1-2
Intestinal motility
Reduced
Biliary function
Immature/ Reduced
Near adult
Congenital heart dx, GERD, prematurity, RDS Decreased gastric emptying time

13. Percutaneous Absorption
Neonatal skin absorption is enhanced by:
Increased BSA to body size ratio (3x adults)
Thinner stratum corneum
Increased skin hydration
Unexpected toxicities from topical products
Apply products SPARINGLY and direct to affected areas only

14. Intramuscular Absorption
Variable due to insufficient muscle contraction and reduced blood flow
Usually delayed in neonates
IM injections
Use only when other routes are not available
Administer in thigh (greatest muscle mass in the neonate)
What products are routinely given IM to neonatal patients?

15. Drugs Affected by Alterations n Absorption
Weak bases: increased oral bioavailability
Penicillin, ampicillin, aminophylline
Weak acids: decreased oral bioavailability
Phenobarbital, phenytoin, acetaminophen
Topical compounds: increased absorption
Hydrocortisone, bacitracin, hexachlorophene, isopropyl alcohol, EMLA preps
EMLA is a topical anesthetic mixture of lidocaine and prilocaine commonly used to lessen pain associated with shots and venipuncture. Increased systemic absorption of prilocaine has led to methemoglobinemia in small infants (<3 months of age)

16. Pharmacokinetic Parameters Absorption Distribution Metabolism Elimination

17. Age Related Changes in Drug Distribution
The volume that drugs distribute into (Vd) is dependent upon:
Body composition
Extent of protein binding
Tissue binding characteristics
Vascular perfusion

18. Drug Distribution Neonates and infants
Increased Vd for water soluble drugs
Decreased Vd for lipid soluble drugs
What are some examples of water soluble drugs and lipid soluble drugs?
Increase dose of water soluble drugs in neonates/infants, decrease dose of lipid soluble drugs
What is the definition of Vd? -Estimate of total amount of drug present in body relative to concentration in blood -Vd helps estimate the LD required to reach a desired plasma conc. - changes in distribution during growth parallel changes in body composition -must give higher mg/kg doses of water soluble drugs and lower mg/kg doses for lipid soluble drugs -What are some examples of water soluble drugs (aminoglycosides) and lipid-soluble drugs (phenytoin, benzodiazepines, ADEK vitamins)? HINT: lipid-soluble drugs cross the BBB

19. Example of Vd vs. Age: Gentamicin
Average Vd (L/kg)
Neonate
0.45
Infant
0.4
Child
0.35
Adolescent
0.3
Adult
0.25 to 0.3

20. Vd Changes Increased Vd may occur for different reasons
Increased total body water
Aminoglycosides
Decreased protein binding
Phenobarbital, phenytoin, theophylline

21. Body Composition Changes
Increased total body water in neonates
Adipose tissue
Increases rapidly during first year of life
Decrease in boys around age 17
Increased BSA to body mass ratio
Decreased muscle mass in infants
Preemie < neonate < child < adolescent/adult

22. Body Composition Age Total Body Water Total Body Fat Preterm infant
86%
 <5%
Term infant
75%
12%
1 year old
60%
30%
Child
55%
Adult
~50%
10-25%
Increased ECF in infants means they have a larger Vd Since the volume of distribution of a drug is measured as a function of its concentration in the extracellular (particularly intravascular) compartment, these changes will result in a relatively higher volume of water soluble drugs in children than in the adult At puberty, females decrease more than males for TBW, ICF and ECF

23. Body Composition
Alteration in protein production and type, affinity, and binding sites in neonates:
↑ bilirubin
↓ serum albumin
Quantitative and qualitative differences exist in protein binding, amt and type of proteins present are different among different age groups The number and affinity of protein binding is decreased in neonates and infants which results in an increased free (unbound) concentration of highly-protein bound drugs such as phenytoin. This increases the activity of the drug in the body.

24. Drug Distribution Differences
↓ protein binding in neonates and infants
↑ free drug available
↑ in drug at the receptor site
↑ in toxicity effects
Decrease in protein binding due to decreased plasma protein concentration, lower binding capacity of protein, decreased affinity of proteins, and competition for certain binding sites by endogenous compounds (bilirubin). The maintenance dose of digoxin is higher in infants than adults due to a lower binding affinity of receptors in the myocardium of the heart for digoxin and increased digoxin-binding sites on neonatal erythrocytes compared with adult erythrocytes. Other info about digoxin: Elimination via renal, metabolic and biliary routes Shorter half-life in infants Metabolism by intestinal flora ¯ in neonates and infants < 2 ­ bioavailability in infants compared to adults

25. Drugs Affected by Alterations in Binding Proteins
Albumin
Bilirubin
ampicilin
ceftriaxone
phenobarbital
phenytoin
sulfonamides
morphine
salicylates
Albumin binds acidic and neutral drugs (decreased in neonates and infants) alpha-1 gp binds basic drugs (decreased in neonates and infants)

26. Bilirubin End product of heme breakdown
↑ in neonates, especially preterm infants
RBC destruction
↓ capacity for glucuronidation
-Ceftriaxone and sulfonamides displace bilirubin from protein binding sites and can lead to the development of kernicterus in neonates. -Ceftriaxone is also eliminated via the bile and can lead to biliary sludging due to the inability of the neonate to eliminate the excess bilirubin. -Kernicterus describes the penetration and deposition of bilirubin in the CNS following its displacement from albumin binding sites which leads to encephalopathy

27. Kernicterus Staining and subsequent damage of the brain by bilirubin
Results from displacing bilirubin from albumin sites
Ceftriaxone and sulfonamides
Widely used in adults
AVOID in infants due to biliary sludging and increased risk of kernicterus

28. Pharmacokinetic Parameters Absorption Distribution Metabolism Elimination

29. Drug Metabolism Slower in the neonate than children and adults due to:
Immature hepatic blood flow
Immature enzymatic pathways
Phase I reactions introduce or expose a functional group on the parent compound to make them available for conjugation and elimination from the body. Phase I reactions are also responsible for converting prodrugs to their active moiety usually via hydrolysis. Phase II reactions lead to formation of a link between a functional group on the parent compound and with glucuronic acid, sulfate, glycine, acetate. These bonds make the compound inactive and available for elimination. Some conjugation reactions may result in active metabolites which we will discuss in a few minutes.

30. Hepatic System Development
Enzyme system activity at birth is only 60-70% compared to adults
Conjugation reactions
Newborn: sulfation, methylation, glycine conjugation
Glucuronidation activity is decreased until ~3 years of age
Adult enzymes values reached by 6 months of age -Decreased hepatic enzyme activity results in prolonged half-lives for drugs that are metabolized by the liver in neonates and infants. (enzyme amt is constant) In a neonate, the sulfation pathway is well developed, but the glucuronidation pathway is underdeveloped. Can you think of drugs that are metabolized via glucuronidation? (acetaminophen, morphine, diazepam) Sulfation? (acetaminophen, steroids, methyldopa)

31. Maturation of Liver and Kidney Function

32. Pharmacokinetic Parameters Absorption Distribution Metabolism Elimination

33. Elimination GFR reaches adult values around 3-5 months of age
GFR is clinically mature by 30 days
Tubular secretion: full function is reached in the toddler years
Reabsorption: reduced at birth, increases with age

34. Genitourinary System ↓ renal blood flow ↓ glomerular filtration rate
↓ tubular secretion at birth
↑ twofold over 1st week of life
↑ tenfold over 1st year of life
↓ tubular reabsorption
1)Renal blood flow inc. with age as CO inc. and PVR dec. (12ml/min at birth) -reaches adult values by 1 year (120 ml/min) 2) GFR doubles by 1-2 weeks of age, but doesn’t reach adult values until 3-5 months 3)Tubular secretion is an active process which reaches adult values by 7-9 months GF>tubular function for 1st 6 months of life b/c tubules are small relative to size of glomeruli at birth 4)Reabsorption reaches adult values by two years of age -passive process -depends on degree of ionization of drug, urinary pH, and urine flow rate -Renal development relates linearly to PCA

35. Drugs Affected by Kidney Function
Glomerular filtration
Aminoglycosides
Vancomycin
Chloramphenicol
Tubular secretion
Penicillins
Sulfonamides
Furosemide
Tubular Reabsorption
Nonionized weak acids and bases
Renal function cannot be determined by creatinine clearance in pediatric patients. Why do you think this is? Remember that creatinine is a measure of muscle which pediatric patients do not have much of so this value is unreliable. This is especially true in the 1st week of life when the newborn baby’s SCr is equal to mom’s SCr and then begins to decline to normal values in 2nd week. How would you monitor renal function in pediatric patients? -UOP, 24-hr CrCl, GFR = Ag renal clearance

36. Medication Management
Aminoglycosides (gentamicin, tobramycin)
Clearance ↓ in the first week of life
Dosing strategies
Extended interval dosing in neonates
Q24-48h
Conventional dosing for infants and children
Q8h

37. Medication Management
Aminoglycoside dosing
Premature neonates
3.5mg/kg/dose Q24-48H
Term neonates (1st week of life)
2.5mg/kg/dose Q12H
Infants and children
2.5mg/kg/dose Q8H
Adults
1-2.5mg/kg/dose Q8-12h OR
5-7mg/kg/dose Q24H
*Dosing for patients with normal renal function for age*

38. Commonly Used Drugs in Pediatrics With Narrow Therapeutic Ranges
Peak
Trough
Gentamicin
5-12 mg/L
<2 mg/L
Tobramycin
Amikacin
20-30 mg/L
5-10 mg/L
Phenytoin
10-20 mg/L
Vancomycin
20-40 mg/L
Digoxin
0.8-2 ng/mL
Phenobarbital
15-40 mg/L
Theophylline
Caffeine
8-20 mg/L

39. Creatinine Clearance Equation
Elimination
Creatinine Clearance Equation
Clcr = kL / Scr
K values for estimating Clcr with the Schwartz Formula
Age Group k
LBW infants < 1 yr
Full term < 1 yr
Children 2-12 yrs
Females yrs
Males yrs

40. Review of Pk Basics Dose changes affect peak values
Peak too high  decrease dose
Peak too low  increase dose
Interval changes affect trough values
Trough too high  increase interval
Trough too low  decrease interval

41. Disease States with Altered Pk
Cystic fibrosis
Increased metabolism
Increased clearance
Cancer
Trisomy 21
Decreased metabolism
Decreased clearance
Birth asphyxia
Sepsis
Increased metabolism
Clearance variable
Celiac or Crohn’s disease
Decreased or inadequate absorption
Burns
Increased clearance

42. Medication Safety in Neonatal and Pediatric Patients

43. Relax, its only a 900 gm Baby!

44. Practical Applications
Medication error prevention
Bedside calculations…LOOK at your patients!
Mg/kg doses, leading zero, trailing zero
Dilutions
Administration and availability problems
Preservatives
Adherence
Resources

45. Medication Error Prevention
Check demographics for ALL patients:
Age
Weight  is it in pounds or kg?
2.2 lbs = 1kg
Diagnosis
Allergies
Current medications
Be aware of changing pharmacokinetics

46. What Should be on the Order?
Medication info
Name, Age, Weight
Allergies
Dose (per weight)
Dosage form
Strength
Route
Frequency
Site of administration

47. Safety Tips Avoid verbal orders unless emergency
Store adult and pediatric products separately
Use unit dose packaging
Use age-appropriate administration devices
Educate, Educate, EDUCATE!

48. Medication Error Prevention
Use individualized dose calculation (mg/kg)
ALWAYS double-check dose calculation
Use caution when dispensing products with multiple concentrations
Gentamicin 2mg/mL (NICU)
Gentamicin 10mg/mL (Peds)
Gentamicin 40mg/mL (Adult)

49. Common Causes of Error Wrong Dosage (Miscalculated)
MD orders Gentamicin 70 mg (7 mg/kg/dose) for 10 kg child
MD intention 7 mg/kg/day (23 mg) Gentamicin
Wrong Dose (Lack of knowledge with drug)
Methadone 0.5 mg oral ordered
Pharmacy sent unit-dose (2 mg/2 ml) Methadone
RN gave entire syringe (2 mg)
Wrong Dose (Lapse of Memory)
MD orders Ancef 80 mg, Gentamicin 1 gm

50. Medication Error: Morphine
9-month old child
Ordered .5mg Morphine IV post-op for pain
Unit Secretary transcribe order as “5mg” Morphine
Experienced nurse gave “5mg” Morphine
Two hours later RN gave another “5mg”Morphine dose
Four hours later…………Child dies
This medication error took place back in May 2000 in Washington, DC.
After review the error with the group. I ask them what the physician could have done to prevent such error. (Usually someone in the group will say use a leading zero).
This type of error has been reported in the literature for the past 25 years and continues to happen.

51. Common Causes of Error Sound A-Like Look A-Like
MD order Pentothal, RN administers Pentobarbital
Code situations: Narcan vs. Norcuron
Look A-Like
Heparin 10,000 units/ml VS. Heparin 10 units/ml
Another example of Misheard order:
During a Code Blue, the MD called for Narcan but, the RN thought he said Norcuron. The patient received Norcuron.
40% of medication errors are related to how the MD prescribes the order. Explain how the pharmacy is trying to proactive on the issue by utilizing the variance forms to provide feedback etc.

52. Medication Error Prevention
Weight should be on every pediatric order
Example: Tylenol dosing for 10kg 1yo boy
Dose is 10-15mg/kg/dose
Correct: Tylenol 100mg (10mg/kg) PO Q6h
Incorrect: Tylenol 10mg/kg PO Q6h

53. Medication Error Prevention
Joint Commission “Do Not Use” Abbreviations
Always include a leading zero
0.6 mg vs. .6 mg
Never include a trailing zero
1 mg vs. 1.0 mg
Units must be spelled out, not written as “u”

54. Neonatal and Pediatric Dilutions
Extemporaneously compounded for accurate delivery
Example: Gentamicin 3.2mg (3.5mg/kg) IV Q24H for 0.9kg neonate
Commercial product: 40mg/ml
Dose would be 0.08mL, difficult to administer
Compounded product: 2mg/ml
Dose would be 1.6mL, easy to administer

55. Additives to Avoid Propylene glycol Benzyl alcohol Sodium benzoate
Ethanol
Sorbitol
Propylene glycol-serum hyperosmolalityand death
Benzyl alcohol- seizures, acidosis, renal/hepatic abnormalities, cardio collapse, death
Sodium benzoate- displaces bilirubin->kernicterus
Ethanol- accumulation, intoxication
Sorbitol- diarrhea, dehydration, electrolyte imbalances

56. Neonatal TPN Peripheral TPN Central TPN Vanilla TPN
Less than 12.5% Dextrose
NO Calcium!!
Central TPN
Up to 25% Dextrose
Watch Calcium/Phosphate ratios
Vanilla TPN
Initial TPN for Grady Babies
Safe for peripheral or central access
PAR level always available in MIP

57. Drug Administration in Neonatal and Pediatric Patients

58. Oral Administration Empty capsules
Crush tablets if chewable form unavailable
Unless time-release or enteric coated product
Mix with soft food, enteral formula, liquids
Concentrated liquids must be diluted
Use oral syringes
Incompatible with IV administration devices
How old must a child be to swallow tablets?
Avoid Luer-lock syringes (may be given IV), teaspoon/tablespoon (inconsistent sizing), and droppers unless calibrated
There is no “appropriate age” where ability to swallow tablets and capsules may be assumed. This ability has been documented in children as young as 3-4 years of age, but many teenagers and adults still struggle with the task. Always ask the caregiver, otherwise assume that liquids and chewable dosage forms are most appropriate for young children.

59. Parenteral Administration
IV/IM administration is best for:
Premature infants
Acutely ill term newborns
All children with nausea, vomiting, diarrhea
IM administration
Always in the thigh in infants
Do not exceed 0.5mL volume per site of injection

60. Parenteral Administration
Keep IV volumes small and concentrated
Infants can only have mL/kg/day of fluid from all sources
Deliver over longer periods of time
ALWAYS flush appropriately!
Flush with twice the volume capacity of the IV administration set/ tubing

61. Rectal Administration
May produce erratic absorption
Use under these circumstances:
Oral administration impossible
Limited or no IV access
Poor compliance with oral administration

62. Counseling Tips: Child
Smile
Speak in soft, soothing voice
Decorate bottles
Use favorite toy to role play
Read labels
Ask how child is feeling
Give child choices
Food or drink
OTC products
Explain importance
Rewards
Praise
Hugs

63. Counseling Tips: Adolescent
Educate
Disease state
Use of medication
Consequences of noncompliance
Locate support groups
Many free or low cost options
Give teen choices
Establish routine
Products, time of day
Provide privacy

64. Neonatal and Pediatric Drug Information Resources

65. Resources: Neofax Dosing for neonates only Brief monographs
Preterm vs. term
Special considerations
Stability data for admixtures
Referenced

66. Resources: Lexi-Comp Pediatric Dosage Handbook
Dosing for all age groups
Detailed monographs
Extemporaneous compounding
Appendices
Nutrition, Tox, ID
Some references

67. Resources: Teddy Bear Book
Neonates and children
Specific to IV administration
Extemporaneous compounding
Compatibility data
Some dosing info
Stability data for admixtures
Referenced

68. Resources: Micromedex
Limited neonatal and pediatric information
Dosing often available
IV compatibility
No information on stability or compounding

69. Questions?