1. Factoid: 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. 1

2. SPECIAL POPULATIONS: PEDIATRICS Lecture #29 2

3. 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 3

4. Pediatric Effects (A) Absorption (D) Distribution (M) Metabolism (E) Excretion Specific Drugs 4

5. General 5

6. A: GI System Gastric acid secretion Bile salt formation Gastric emptying time Intestinal motility Bowel length and effective absorptive surface Microbial flora 6

7. A: Stomach increase in gastric pH – neonates, infants, young children – pH = 6-8 at birth (vaginal delivery, amniotic fluid) – increases to body weight ~2-3 years increase for basic drugs – penicillin decrease for weakly acidic drugs – phenytoin, phenobarbital 7

8. A: Small Intestines 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 soluble drugs or vitamins.  -glucuronidase activity increases (breast milk) 8

9. A: Microbial Flora Breast Fed Infants – Digestive Tract Difidobacterium – Antimicrobial Factors – Intestinal Lumen more acidic – Bifidobacterium  Less Prone to Infection Formula Fed Infants – Digestive Tract Bacteriodes – No antimicrobial factors Streptococcus and Clostridium – Intestinal Lumen closer to neutral pH – More prone to infections, diarrhea and allergies Vaginal Birth vs. Caesarian Section 9

10. D: Body Composition 10

11. D: Blood Volume Premature infants- 98 mL/kg At 1 year- 86 mL/kg > 1 year- 77 mL kg 11

12. D: Protein Binding 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 Volume Distribution (V) – reduced  -1-acid glycoprotein (orosomucoid) increased Volume Distribution (V) of basic drugs 12

13. M Liver metabolism – All enzymes, but activity reduced – Phase I (20-70%) of adult (neonate) reduced hydroxylation and N-demethylation reduction capacity the same increased methylation – Phase II reaches adult values in 3-4 years reduced conjugation – UGTs- chloramphenicol-”gray baby syndrome” 13

14. M 14

15. M 15

16. M 16

17. E: 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 17

18. E: Creatine Concentrations Infants – Normal: 2.0 mg/L (0.2 mg/dL) – Kidney Disease: >20.0 mg/L (2 mg/dL) Adults Males: 6-12 mg/L (0.6-1.2 mg/dL) Females: 5-11 mg/L (0.5-1.1 mg/dL) One Kidney: 8-19 mg/L (0.8-1.9 mg/dL) Weight Lifter: > 12 mg/L (1.2 mg/dL) Disease >100 mg/L (10 mg/dL) 18

19. E: Creatine Clearance 19

20. E: 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 20

21. E: 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 21

22. 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 – average body surface areas of men and women age 25 prior to actuarial tables 22

23. Pediatric Effects (A) Absorption (D) Distribution (M) Metabolism (E) Excretion Specific Drugs 23

24. Aminoglycosides (Antibiotic) Streptomycin Gram-negative antibacterial therapeutic agent Examples Escherichia Coli (E. coli) Salmonella Shigella 24

25. 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 25

26. Aminoglycosides: Cystic Fibrosis Cystic fibrosis transmembrane conductance regulator (CFTR) 26

27. 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? 27

28. Vancomycin 28

29. Vancomycin 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 29

30. Digoxin (Lanoxin) Cardiomyocyte TN-C = Troponin C Foxglove known since the middle ages Control Heart Rate 30

31. 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 31

32. Digoxin Dosing 32

33. Theophylline caffeine PDE=Phosphodiesterase PKA=Protein Kinase A 33

34. 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 34

35. Dosing 35