IMM 31: Pediatric Pharmacokinetics Flashcards
Oral Drug Absorption
- higher gastric pH – decreased absorption of ‘acidic’ drugs
- less peristalsis – slower gastric emptying
- reduced gastric motility – most drugs absorbed in small intestine, longer time to achieve max concentration (ie. acetaminophen)
- lack of intestinal flora – altered oral bioavailability of drugs (ie. digoxin)
- decreased first pass effect – approaches adult values at 6-12 months
Rectal Absorption
- erratic absorption
- retention time
- bioavailability – depends on formulation used (solid vs. liquid)
- venous drainage for lower GI tract – superior rectum undergoes 1st pass metabolism, lower rectum bypasses portal circulation
- lipophilic drugs best PR absorption – ie. barbituate, benzodiazepine
Percutaneous Drug Absorption
- larger BSA: body mass ratio
- better hydration and perfusion
- thinner stratum corneum – increased absorption of topical agents, too erratic for predictable drug delivery, potential for systemic toxicity
Drug Absorption Summary
- erratic absorption
- prolonged drug exposure in stomach increases time to absorption and Cmax
What is drug distribution influenced by?
- body composition and solubility of drug in water vs. fat
- protein binding
- body compartment sizes
- hemodynamic factors – cardiac output
- regional perfusion
- membrane permeability
Body Composition
Premature Infant
- total body water
- ECF water
- fat
- total body water: 80-85%
- ECF water: 40-45%
- fat: < 5%
Body Composition
Term Neonate
- total body water
- ECF water
- fat
- total body water: 75-80%
- ECF water: 45-55%
- fat: 10-15%
Body Composition
6 months
- total body water
- ECF water
- fat
- total body water: 65-70%
- ECF water: 20-25%
- fat: 15-20%
Body Composition
12 months
- total body water
- ECF water
- fat
- total body water: 60-65%
- ECF water: 18-20%
- fat: 20-25%
Body Composition
Adolescents
- total body water
- ECF water
- fat
- total body water: 55-60%
- ECF water: 25-30%
- fat: 15-30%
Protein Binding
- age at which protein binding reaches adult levels and function is unknown (approximately 1 year)
- clinical importance for drugs with 80-90% protein binding
- albumin concentration and binding capacity and affinity is lower at birth, and increases with age
Protein Binding
What does a lower albumin concentration, binding capacity, and affinity mean for drugs?
reduced binding of ceftriaxone, penicillins, phenytoin, sulfa drugs
Protein Binding
α1-acid glycoprotein
- neonates 33% of adult levels
- reduced binding of drugs such as lidocaine and propranolol
- reaches adult levels by 1 year of age
Protein Binding
Bilirubin
- ↑ in neonates
- binds to albumin
- albumin has lower affinity for bilirubin than in adults
- many drugs displace bilirubin from albumin (higher binding affinity), resulting in kernicterus
Membrane Permeability
What body sites is it difficult to penetrate?
- CNS – blood brain barrier
- eye
- sinuses
- lungs
- bones
- joints
Distribution Summary
- higher fat in infants –↑ volume of distribution of lipophilic drugs (ie. sedatives, phenobarbital)
- larger proportion of ECF in neonates and
infants – ↑ volume of distribution of hydrophilic drugs (ie. aminoglycosides) - permeability of many membranes ↑ – ↑ Vd and penetration
Phase I Metabolism
(see slides)
- phase I reactions generally decrease in neonates
- reach adult capacity at various times
Phase II Metabolism
(see slides)
- methylation and sulfation ‘good’ in neonates
- glucuronidation and acetylation poor in neonates (increase by 2 months to 3 years)
Metabolism Summary
- caution in neonates and infants regarding different metabolic pathways, dosage adjustments
Elimination
Gentamicin
eliminated almost entirely unchanged by the kidney
Elimination Summary
renal function decreased at birth
- GFR ↑ in first 1-2 weeks of life
- tubular secretion: 6-8 months
- tubular reabsorption: 1-2 year
renal elimination increases in infants, children, and adolescents relative to adults
Impact of Developmental PK on Drug Dosing in Neonates
Absorption – PO, PR IM, Inhalation
unclear effect on drug dosing
Impact of Developmental PK on Drug Dosing in Neonates
Absorption – Transdermal Route
increased absorption, use caution
Impact of Developmental PK on Drug Dosing in Neonates
Distribution – Water-Soluble Drugs
larger single dose per kg
Impact of Developmental PK on Drug Dosing in Neonates
Distribution – Highly Protein-bound Drugs
smaller single dose per kg
Impact of Developmental PK on Drug Dosing in Neonates
Metabolism
less frequent dosing and/or lower total daily dose per kg
Impact of Developmental PK on Drug Dosing in Neonates
Elimination
less frequent dosing and/or lower total daily dose per kg
What medications should be avoided in neonates?
- sulfa drugs
- ceftriaxone
- nitrofurantoin
- erythromycin (systemic)
Why should sulfa drugs be avoided in neonates?
displaces bilirubin from albumin, resulting in kernicterus
Why should ceftriaxone be avoided in neonates?
- displaces bilirubin from albumin, resulting in kernicterus
- biliary sludge
- interaction with calcium (ie. TPN)
Why should nitrofurantoin be avoided in neonates?
hemolytic anemia
Why should erythromycin (systemic) be avoided in neonates?
pyloric stenosis
What preservatives/excipients should be avoided in neonates?
- benzyl alcohol
- propylene glycol
- ethanol
Why should benzyl alcohol be avoided in neonates?
neonatal gasping syndrome (metabolic acidosis, neurologic deterioration, gasping respirations)
Why should propylene glycol be avoided in neonates?
- hemolysis
- central nervous system depression
- hyperosmolality
- lactic acidosis
Why should ethanol be avoided in neonates?
- central nervous system depression
- respiratory depression
Ampicillin
What PK factors explain the differences in dosing between the various age groups?
(see slides)
Metronidazole
What PK factors explain the differences in dosing between the various age groups?
(see slides)
Morphine
What PK factors explain the differences in dosing between the various age groups?
(see slides)
Vancomycin
What PK factors explain the differences in dosing between the various age groups?
(see slides)
