PK/PD - Pediatrics Flashcards
Age Classifications
Neonates: Newborn to 1 month Infants: 1 month to 2 years Children: 2 years to 12 years Adolescents: 12 to 16 years old **FDA established**
Pregnancy Classifications
Term Pregnancy: 37-40 weeks
Premature Pregnancy: < 37 weeks
Viable Pregnancy: > 24 weeks
Age Classfications
Gestational Age: Time of conception to birth
Postnatal Age: Age since birth
Postmenstrual Age: GA + PNA
Weight Classifications
Low Birth Weight: < 2500 g: < 35 weeks
Very Low Birth Weight: < 1500 g: < 30 weeks
Extremely Low Birth Weight: < 1000 g: < 27 weeks
Fetal Development
- Embryonic Periods: organogenesis, sensitivity to drug exposure
- Fetal Periods: organ maturation, less sensitive to drug exposure but still significant
- *Can affect PK**
Liver Development
- CYP content ~30-60% of adult values
- Starts developing around week 4 and continues to develop throughout gestation
Renal Development
- Develops weeks 5-15
- Development continues until completed at week 24
- Functionally matures at birth - can be affected by utero drug exposure
Milestones
- Weight: doubles in 1st 6 months, triples by first year
- Body composition: fat, protein, water percentage are constantly changing
- Organ maturation: major organs mature in the first 2 years
Pediatric PK Considerations
ADME parameters vary greatly by age, even when normalized by weight
Pediatric PD Considerations
Some evidence supports differing receptor sensitivity and density
PK - Absorption
- Total absorption is driven by the rate (affects onset) and extent (determines effective dose) of absorption
- Drug enters body for therapeutic effects at oral/GI, transmucosal, transdermal, and IM routes
- Matters since body composition and development stages affect absorption
Absorption - Oral/GI - pH
Normal Adult pH: 1.5-3.5
Birth d/t amniotic fluid pH: 6-8
24-48 hours pH: 1-3
Day 8 pH: ~7
Absorption - Oral/GI - Secretions
-HCl secretions mature slowly
-Reaches adult levels at about 2 years of age
-Every drug is optimally absorbed or activity at certain pH
EX: beta lactam antibiotic: high pH: high bioavailability
EX: Weak acids (APAP, Phenytion): high pH: low bioavailability
Absorption - Oral/GI - Gastric Motility/Emptying
-Small intestine = major site of absorption
-Prolonged in neonates which affects the rate of absorption
EX: APAP, digoxin has delayed onset
-Clinical factors: gastroenteritis, diarrhea
Absorption - Oral/GI - Additional Factors
- Intestinal SA - small gut: decreased SA: decreased absorption
- Diet
- Biliary function and pancreatic enzymes are underdeveloped which affects lipophilic drug solubility and absorption
Absorption - Oral/GI - Intestinal Metab/Enzymes
-Metabolizing enzymes and drug transporters re not well elucidated
EX: Gabapentin has decreased absorption in those under 5 years old from decreased L-amino transporter activity
EX: Decreased P-gp activity in neonates
Absorption - Transmucosal
- SL, nasal, rectal
- ~50% of rectal blood flow bypasses first pass metabolism
- Dose loss d/t expulsion
- Often convenient: Midazolam, APAP
Absorption - Skin
Neonates and infants have increased skin permeability due to:
-Increases in skin hydration
-Thinner stratum corneum
-Increased subcutaneous perfusion
-Increased BSA:Mass ratio
EX: Steroids (topical OTC hydrocortisone)
Absorption: IM
-Decreased muscle mass: decreased absorption tissue
-Poor muscle tone: decreased blood flow musculature
-More capillaries
-Evidence shows variable and decreases in absorption
EX: Antibiotics, phenobarbital
Advantages if slow absorption in preferred like with Vitamin K at birth
Distribution
- Vd is a ratio of total drug in body to the drug measured in the plasma
- Depends on hydrophilicity/lipophilicity, plasma protein binding, tissues binding of drug
- Drug disperses through body in compartments
- Understanding Vd helps guide loading doses by considering CL and affects on half lives
- Hydro/lipophilicity of drug determines which compartments it does in to
Distribution - Pediatric Compartment Size
- Changes relative to age
- Total body water (decreases with age) and body fat (increases with age) are examples
Total Body Water Changes
Preterm neonates: 85%
Term neonates: 75%
1 year old: down to 60%
Total Body Fat Changes
Preterm neonates: 2%
Neonates: 10-15%
1 year: 20-25%
Distribution - Plasma Protein Binding
- Neonates have decreases protein binding since there is less proteins, lower affinities, and more competing substrates like bilirubin and FFA
- Increases Vd, protein maturation occurs at about 10-12 months
