1. Special Populations: Pediatrics Arthur G. Roberts

2. Is there a difference in blood flow (Q) between an athlete and non-athlete? Blood flow increases during exercise. At rest, blood flow is similar to non-athletes, except that it takes less beats/min to push the same amount of blood.

3. Review: Creatine Clearance Used to measure renal function and estimate glomulerular filtration rate (GFR) Creatine- breakdown product of creatinine, part of muscle Measure – blood and urine

4. Age Classifications Neonate- to 1 month post utero Infant- 1 month to 2 years Child- 2 and 12 years Pre-adolescent and adolescent- 13 to 17 years Adult- >18 years of age

5. Absorption Affected Gastric acid secretion Bile salt formation Gastric emptying time Intestinal motility Bowel length and effective absorptive surface Microbial flora

6. Effects on Absorption decrease in gastric pH – neonates, infants, young children – pH = 6-8 at birth (vaginal delivery, amniotic fluid) – increases to body weight ~2-3 years increase of basic drugs – penicillin decrease of weakly acidic drugs – phenytoin, phenobarbital

7. Effects on Absorption decrease gastric and intestinal motility (neonates and infants) – Peristalsis absent in first 2-4 days – Adult values reached in in 6-8 months – Prolonged diarrheal episodes may contribute decrease bile acids by 50% (neonates) – impaired absorption of lipid solubile drugs or vitamins.  -glucuronidase activity increases (breast milk)

8. Effects of Distribution: Body Composition

9. Effects on Distribution: Blood Volume Premature infants- 98 mL/kg At 1 year- 86 mL/kg > 1 year- 77 mL kg

10. Effects on Distribtuion Plasma Protein Binding – reduced Albumin (bilirubin and various drugs) Newborn- 3.1 g/dL (66% of adult) 1-3 years- 3.8 g/dL 4-6 years- 4.4 g/dL >7 years- 4.7 g/dL reduced affinity increased V d – reduced  -1-acid glycoprotein (orosomucoid) increased V d of basic drugs

11. Metablism and Elimination Liver metabolism – All enzymes, but activity reduced – Phase I (20-70%) of adult (neonate) reduced hydroxylation and N-demethylation capacity reduction the same increased methylation – Phase II reaches adult values in 3-4 years reduced conjugation – UGTs- chloramphenicol-”gray baby syndrome”

12. Metabolism and Elimination: Renal Clearance Creatine Clearance – (1 day)- 18 mL/min/1.73 m 2 – (6 days)- 36 mL/min/1.73 m 2 – (1-5 months) – 70 mL/min/1.73 m 2 – (6-11 months) – 100 mL/min/1.73 m 2 – (adult)-112 mL/min/1.73 m 2

13. Metabolism and Elimination: Renal Clearance Decreased renal function 20-40% of adult Decreased glomerular filtration rate – ~40 mL/min/1.73 m 2 (neonate) premature infants even lower Decreased Tubular Secretion and transporter- mediated Reabsorption Increased t 1/2, increase dosing interval

14. Estimating GFR (Creatine Clearance): Schwartz equations k = 0.33 in preemie infants k= 0.45 in infants to 1 year k = 0.55 to 13 years of age and female >13 years k=0.70 males >13 years http://www.pharmacologyweekly.com/app/medical-calculators/pediatric-gfr-calculator- renal-function

15. What the hell is 1.73 m 2 ? normalization refers to standardized body surface area of a 70 kg man – from 8 children, 7 adults in 1928 – areas of mean and women age 25 prior to actuarial tables

16. Aminoglycosides (Antibiotic) Streptomycin Gram-negative antibacterial therapeutic agent Examples Escherichia Coli (E. coli) Salmonella Shigella

17. Aminoglycosides: Baby’s Reaction Neonates – increased V d (0.5-0.6 L/kg) (dosage?) – increased t 1/2 (dosing interval?) Infants and children – increased V d (0.4-0.5 L/kg) (dosage?) – t 1/2 normalizes (dosing interval) Adults – V d (0.25-0.35 L/kg) – t 1/2 (Streptomycin) = 3 hours – dosing interval = 8-12 hours http://www.globalrph.com/aminoglycosides.htm

18. Aminoglycosides: Cystic Fibrosis Cystic fibrosis transmembrane conductance regulator (CFTR)

19. Aminoglycosides: Cystic Fibrosis Increased Vd – increased lean body mass/kg – increased tissue binding 25% Increased Cl, shorter t 1/2 (GFR) dosing? and dosing interval?

20. Vancomycin

21. Neonates – Increased Vd (0.75 L/kg) adult 0.62 L/kg – Increased T 1/2 6-11 hours adults 4-6 hours Infants and children – Clearance 2-3x higher compared to adults – t 1/2 : 3-4 hours in infants – t 1/2 :2-3 hours in children

22. Digoxin (Lanoxin) Cardiomyocyte TN-C = Troponin C Foxglove known since the middle ages Control Heart Rate

23. Digoxin Neonates – Decreased Cl and Vd – Digoxin-like immunoreactive substance (DLIS) associated with cardiomyopathy structure similar to digoxin interferes with therapy baseline concentration may be required Infants – Increased Vd 11.9 L/kg Adult Vd 6L/kg

24. Digoxin Dosing

25. Theophylline caffeine PDE=Phosphodiesterase PKA=Protein Kinase A

26. Theophylline Indications in Pediatrics – Asthma – Premature apnea/bradycardia – Bronchopulmonary dysplasia Neonates – increased Vd, decreased Cl – lower loading and maintenance doses Children (1-4 years old) – increased Cl

27. Dosing