11/12- Pediatric Developmental Pharmacology Flashcards
Over __% of FDA approved drugs DO NOT have neonatal labeling and this has resulted in things like what?
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
What are some of the challenges in neonatal pharmacotherapy?
- Lack of safety and efficacy data
- Lack of neonatal dosing guidelines
- Lack of commercially available formulations
When do the most dramatic changes in developmental pharmacokinetics occur?
First 12 mo of life
- Ongoing process throughout infancy, childhood, and adolescence
What are some physiological differences that affect pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What are the different methods of absorption?
- Oral
- Intramuscular
- Transdermal
- Rectal
- Intravenous
What age-dependent factors affect oral administration?
Rate and extent extent of GI absorption are influenced by age related changes
- pH
- Gastric emptying time
- Intestinal integrity
- GI motility
How does gastric pH change in development?
- “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)
How does gastric emptying time change in development?
- 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
Describe the intestinal integrity in development
- What factors would increase drug absorption
- Describe the role of smolality
- 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
What are some disease states affecting GI absorption?
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 (↓)
What are the developmental adaptations with oral absorption?
- Established doses have compensated for differences
- Monitor blood concentrations for drugs with narrow therapeutic ranges
What factors influence absorption of IM administered drugs?
- Skeletal muscle blood flow
- Muscle size
- Muscle activity
__ is preferred over IM administration
IV is preferred over IM administration
What is the preferred location for IM administration?
Anterolateral thigh
- Not butt, because you may compromise the sciatic nerve
What factors influence absorption of transdermally administered drugs?
- Skin thickness
- Skin hydration
- Surface area of skin
- Skin damage
Why are transdermal drugs not preferred?
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
Describe rectal administration in development
- How is bioavailability altered
- Risks
- 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
Quick aside on volume of distribution…
- 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
How do fluid compartments change during development?
- TBW and extracellular water percentages decrease
- Adipose tissue % increases
What do the increased % TBW and extracellular water mean for pediatric patients?
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
Only ___ (bound/unbound) drug is pharmacologically active
Only unbound drug is pharmacologically active
- Neonatal patients have qualitative and quantitative differences in protein binding
How does protein binding change in development?
There is decreased protein binding in neonates vs. adults (more free drug)
Ex) 55 year old healthy male vs. 8 month old healthy male
- Total phenytoin level = 18 mcg/mL
- Who has higher FREE phenytoin level?
The neonate (?)
Decreased albumin levels means what for drugs? Ex?
More displacement of drugs/endogenous substances
- Ex) Ceftriaxone & SMP/TMX
- Displace bilirubin from albumin binding sites
- ↑ free bilirubin in bloodstream and risk of kernicterus
What disease states increase volume of distribution?
- Cystic fibrosis
- Malignancies
- Liver failure with ascites
- Septic shock
- Anasarca
What disease states decrease volume of distribution?
Dehydration
What factors may cause reduced hepatic metabolism (recall, the liver is the major site of drug biotransformation)?
- 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
What are phase I reactions?
Conversion of drug molecules to more polar molecules
- Oxidation
- Reduction
- Hydrolysis
What does drug oxidation?
- Cytochrome P450 system
- Different developmental patterns
What are phase II reactions?
- Synthetic or conjugation reactions
- Combine drug substrate with endogenous molecules to form even more water soluble metabolites
- Sulfation
- Acetylation
- Glucuronidation
Describe the factors involved in glucuronide conjugation and how this is developmentally relevant (don’t need to memorize drugs)
- 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
Describe the factors involved in glycine conjugation and how this is developmentally relevant
- 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)
Describe the factors involved in sulfation and how this is developmentally relevant
- 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
Describe the factors involved in acetaminophen metabolism and how this is developmentally relevant
Metabolized via sulfation rather than glucuronidation as in adults
What disease states increased hepatic clearance? Decrease?
Increase:
- Cystic fibrosis
Decrease
- Congenital heart clearance
- Birth asphyxia
- Sepsis
What factors contribute to elimination of drugs?
- Renal blood flow
- ↑ During first few days of life
- Glomerular filtration
- Tubular secretion
- Tubular reabsorption
Serum creatinine at birth reflects the concentration of the mother. What happens over time?
- 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
Describe changes in glomerular filtration rate (GFR)/creatinine clearance
- 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
Describe changes in tubular activity as it contributes to secretion
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
Describe renal handling of phenobarbital
- 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)
What do these renal function particulars mean for the neonate?
- Decreased renal clearance
- Increased drug half life
- Increased dosing intervals
What disease states increase renal clearance? Decrease?
Increased renal clearance:
- Cystic fibrosis
Decreased renal clearance:
- Renal disease/failure
- Asphyxia
- Indomethacin therapy
- Congenital heart disease/decreased cardiac output
- Sepsis
PK/PD Summary
- Varied absorption depending on different factors and routes of administration
- Increased volume of distribution
- Decreased protein binding
- Decreased hepatic metabolism
- Decreased renal clearance
Rando chart of plasma protein binding
