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a_ARTS > 11/12- Pediatric Developmental Pharmacology > Flashcards

11/12- Pediatric Developmental Pharmacology Flashcards

1
Q

Over __% of FDA approved drugs DO NOT have neonatal labeling and this has resulted in things like what?

A

Over 90% of FDA approved drugs DO NOT have neonatal labeling and this has resulted in things like:

  • Grey baby syndrome (Chloramphenicol)
  • Kernicterus (Trimethoprim/Sulfamethoxazole)
  • Unconjugated bilirubin accumulating in the brain causing encephalopathy
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2
Q

What are some of the challenges in neonatal pharmacotherapy?

A
  • Lack of safety and efficacy data
  • Lack of neonatal dosing guidelines
  • Lack of commercially available formulations
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3
Q

When do the most dramatic changes in developmental pharmacokinetics occur?

A

First 12 mo of life

  • Ongoing process throughout infancy, childhood, and adolescence
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4
Q

What are some physiological differences that affect pharmacokinetics?

A

- Absorption

- Distribution

  • Metabolism
  • Excretion
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5
Q

What are the different methods of absorption?

A
  • Oral
  • Intramuscular
  • Transdermal
  • Rectal
  • Intravenous
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6
Q

What age-dependent factors affect oral administration?

A

Rate and extent extent of GI absorption are influenced by age related changes

  • pH
  • Gastric emptying time
  • Intestinal integrity
  • GI motility
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7
Q

How does gastric pH change in development?

A
  • “Relative achlorhydria” (pH > 4) in neonates
  • Reaches adult value around 2 years of age
  • Drug absorption
  • Acidic pH ↑ absorption of acidic drugs (phenobarbital, phenytoin)
  • Basic pH ↑ absorption of basic drugs (penicillin, ampicillin)
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8
Q

How does gastric emptying time change in development?

A
  • Most absorption at the small intestine (like adult)
  • Motility is irregular -> difficult to predict the extent or time for peak drug absorption
  • Factors affecting gastric emptying time
  • Gestational age, disease states, dietary intake
  • Reaches adult values at 6-8 months of age
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9
Q

Describe the intestinal integrity in development

  • What factors would increase drug absorption
  • Describe the role of smolality
A
  • Immature or altered permeability of intestinal mucosa increases drug absorption
  • GI integrity is influenced by drug osmolality (high medication osmotic load is attributable to inactive additives like preservatives or flavorings)
  • ↑ Osmolality destroys GI integrity
  • ↑ Risk of necrotizing enterocolitis
  • Avoid high osmolality medications until full enteral feeds are achieved
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10
Q

What are some disease states affecting GI absorption?

A

Gastric acid secretion

  • Surgical removal of small bowel

Delayed gastric emptying

  • Pyloric stenosis
  • Congenital heart disease

Intestinal transit time

  • Protein calorie malnutrition (↑)
  • Thyroid disorders (hypo: ↑ ; hyper:↓)
  • Diarrhea (↓)
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11
Q

What are the developmental adaptations with oral absorption?

A
  • Established doses have compensated for differences
  • Monitor blood concentrations for drugs with narrow therapeutic ranges
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12
Q

What factors influence absorption of IM administered drugs?

A
  • Skeletal muscle blood flow
  • Muscle size
  • Muscle activity
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13
Q

__ is preferred over IM administration

A

IV is preferred over IM administration

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14
Q

What is the preferred location for IM administration?

A

Anterolateral thigh

  • Not butt, because you may compromise the sciatic nerve
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15
Q

What factors influence absorption of transdermally administered drugs?

A
  • Skin thickness
  • Skin hydration
  • Surface area of skin
  • Skin damage
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16
Q

Why are transdermal drugs not preferred?

A

Increased absorption

  • Newborn’s ratio of skin surface area to body weight is approximately 3 times that of an adult Possible systemic toxicity
  • Corticosteroids, alcohol, diphenhydramine
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17
Q

Describe rectal administration in development

  • How is bioavailability altered
  • Risks
A
  • Effective
  • Bioavailability may be increased for some drugs
  • Bypass first pass metabolism (lower rectum)
  • Diazepam and acetaminophen
  • Not for routine use
  • Risk of perforation of intestinal wall
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18
Q

Quick aside on volume of distribution…

A
  • Volume of distribution is a concept used to explain the drug concentrations we achieve
  • Magnitude of Vd provides insight into drug distribution
  • Large Vd → absorption in fat or protein binding
  • Small Vd → distribution in plasma only
19
Q

How do fluid compartments change during development?

A
  • TBW and extracellular water percentages decrease
  • Adipose tissue % increases
20
Q

What do the increased % TBW and extracellular water mean for pediatric patients?

A

Recall: C = dose/volume

  • Larger doses of hydrophilic and smaller doses of lipophilic drugs are required in neonates
  • Ex) smaller doses of Gentamicin given with increasing age
21
Q

Only ___ (bound/unbound) drug is pharmacologically active

A

Only unbound drug is pharmacologically active

  • Neonatal patients have qualitative and quantitative differences in protein binding
22
Q

How does protein binding change in development?

A

There is decreased protein binding in neonates vs. adults (more free drug)

23
Q

Ex) 55 year old healthy male vs. 8 month old healthy male

  • Total phenytoin level = 18 mcg/mL
  • Who has higher FREE phenytoin level?
A

The neonate (?)

24
Q

Decreased albumin levels means what for drugs? Ex?

A

More displacement of drugs/endogenous substances

  • Ex) Ceftriaxone & SMP/TMX
  • Displace bilirubin from albumin binding sites
  • ↑ free bilirubin in bloodstream and risk of kernicterus
25
Q

What disease states increase volume of distribution?

A
  • Cystic fibrosis
  • Malignancies
  • Liver failure with ascites
  • Septic shock
  • Anasarca
26
Q

What disease states decrease volume of distribution?

A

Dehydration

27
Q

What factors may cause reduced hepatic metabolism (recall, the liver is the major site of drug biotransformation)?

A
  • Decreased hepatic blood flow
  • Decreased cellular uptake of drugs
  • Decreased biliary excretion
  • Decreased hepatic enzyme capacity
  • Immature enzyme activity Phase I and Phase II reactions
28
Q

What are phase I reactions?

A

Conversion of drug molecules to more polar molecules

  • Oxidation
  • Reduction
  • Hydrolysis
29
Q

What does drug oxidation?

A
  • Cytochrome P450 system
  • Different developmental patterns
30
Q

What are phase II reactions?

A
  • Synthetic or conjugation reactions
  • Combine drug substrate with endogenous molecules to form even more water soluble metabolites
  • Sulfation
  • Acetylation
  • Glucuronidation
31
Q

Describe the factors involved in glucuronide conjugation and how this is developmentally relevant (don’t need to memorize drugs)

A
  • Glucuronide conjugation is completed by Uridine diphosphate (UDP)-glucuronosyltransferase (UGT)
  • Activity reduced at birth
  • Reached adult levels around 6-18 months
  • Bilirubin, morphine, APAP, corticosteroids and lorazepam undergo glucuronidation
  • Historical example: Chloramphenicol tragedy
32
Q

Describe the factors involved in glycine conjugation and how this is developmentally relevant

A
  • Glycine conjugation is decreased in newborns
  • Increases to adult levels by approximately 8 weeks of age
  • Historical example: Neonatal gasping syndrome (and death)
  • Caused by benzyl alcohol metabolism problems (alcohol dehydrogenase gets it to benzoic acid which then gets glycine conjugation)
33
Q

Describe the factors involved in sulfation and how this is developmentally relevant

A
  • Sulfotransferase system is fairly well developed at birth (decreased, but probably the most mature of the Phase II reactions)
  • May compensate for limited function of other pathways (may not get back to baseline, but helps)
  • Clinical example: APAP
34
Q

Describe the factors involved in acetaminophen metabolism and how this is developmentally relevant

A

Metabolized via sulfation rather than glucuronidation as in adults

35
Q

What disease states increased hepatic clearance? Decrease?

A

Increase:

  • Cystic fibrosis

Decrease

  • Congenital heart clearance
  • Birth asphyxia
  • Sepsis
36
Q

What factors contribute to elimination of drugs?

A
  • Renal blood flow
  • ↑ During first few days of life
  • Glomerular filtration
  • Tubular secretion
  • Tubular reabsorption
37
Q

Serum creatinine at birth reflects the concentration of the mother. What happens over time?

A
  • It then falls over time to a lower normal value.
  • It declines rapidly in the first week of life in term infants and over two to three weeks in preterm infants to nadir values
38
Q

Describe changes in glomerular filtration rate (GFR)/creatinine clearance

A
  • In terms newborns, GFR increases markedly after birth, doubling by 1 -2 weeks postnatal age (still only 50 at 3 wks)
  • GFR does not reach adult values until 3-5 mo
  • A normal GFR should not be assumed in older preterm infants even up to 1-2 years postnatal age.
  • The younger the patient is, the less renal function they have and the longer it takes them to reach the full expected values of a pediatric patient
39
Q

Describe changes in tubular activity as it contributes to secretion

A

Secretion:

  • 20-30% of adult values at birth
  • Doubles over first 7 days of life
  • Reaches adult values by 30-40 weeks postnatal age
  • Furosemide, penicillins, thiazides, morphine
40
Q

Describe renal handling of phenobarbital

A
  • Filtered in the glomerulus
  • Reabsorbed and secreted by the tubular cell
  • Half-life is prolonged at birth (43-217 hours) – clearance increases significantly during the neonatal period with half-life decreasing to approximately 45 hours at 28 days
  • Dosing example: Neonates: 3-4 mg/kg/DAY given once daily; assess serum concentrations; increase to 5 mg/kg/DAY if needed (usually by second week of therapy)
41
Q

What do these renal function particulars mean for the neonate?

A
  • Decreased renal clearance
  • Increased drug half life
  • Increased dosing intervals
42
Q

What disease states increase renal clearance? Decrease?

A

Increased renal clearance:

  • Cystic fibrosis

Decreased renal clearance:

  • Renal disease/failure
  • Asphyxia
  • Indomethacin therapy
  • Congenital heart disease/decreased cardiac output
  • Sepsis
43
Q

PK/PD Summary

A
  • Varied absorption depending on different factors and routes of administration
  • Increased volume of distribution
  • Decreased protein binding
  • Decreased hepatic metabolism
  • Decreased renal clearance
44
Q

Rando chart of plasma protein binding

A

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