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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.

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SPECIAL POPULATIONS: PEDIATRICSLecture #29

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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

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Pediatric Effects

• (A) Absorption• (D) Distribution• (M) Metabolism • (E) Excretion• Specific Drugs

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General

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A: GI System

• Gastric acid secretion• Bile salt formation• Gastric emptying time• Intestinal motility• Bowel length and effective absorptive surface• Microbial flora

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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

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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.• b-glucuronidase activity increases (breast milk)

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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

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D: Body Composition

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D: Blood Volume

• Premature infants- 98 mL/kg• At 1 year- 86 mL/kg• > 1 year- 77 mL kg

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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 a-1-acid glycoprotein (orosomucoid)• increased Volume Distribution (V) of basic drugs

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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”

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M

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M

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M

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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

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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)

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E: Creatine Clearance

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E: Renal Clearance

• Decreased renal function 20-40% of adult• Decreased glomerular filtration rate– ~40 mL/min/1.73 m2 (neonate)• premature infants even lower

• Decreased Tubular Secretion and transporter-mediated Reabsorption

• Increased t1/2, increase dosing interval

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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

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What the hell is 1.73 m2?

• 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

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Pediatric Effects

• (A) Absorption• (D) Distribution• (M) Metabolism • (E) Excretion• Specific Drugs

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Aminoglycosides (Antibiotic)

Streptomycin

Gram-negative antibacterial therapeutic agent

Examples• Escherichia Coli (E. coli)• Salmonella• Shigella

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Aminoglycosides: Baby’s Reaction

• Neonates– increased Vd (0.5-0.6 L/kg) (dosage?)

– increased t1/2 (dosing interval?)

• Infants and children– increased Vd (0.4-0.5 L/kg) (dosage?)

– t1/2 normalizes (dosing interval)

• Adults– Vd (0.25-0.35 L/kg)

– t1/2 (Streptomycin) = 3 hours– dosing interval = 8-12 hours

http://www.globalrph.com/aminoglycosides.htm

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

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Aminoglycosides: Cystic Fibrosis

• Increased Vd– increased lean body mass/kg– increased tissue binding

• 25% Increased Cl, shorter t1/2 (GFR)• dosing? and dosing interval?

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Vancomycin

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Vancomycin

• Neonates– Increased Vd (0.75 L/kg)• adult 0.62 L/kg

– Increased T1/2 6-11 hours• adults 4-6 hours

• Infants and children– Clearance 2-3x higher compared to adults– t1/2: 3-4 hours in infants

– t1/2:2-3 hours in children

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Digoxin (Lanoxin)

Cardiomyocyte

TN-C = Troponin C

Foxglove

known since the middle ages

ControlHeartRate

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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

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Digoxin Dosing

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Theophylline

caffeine

PDE=PhosphodiesterasePKA=Protein Kinase A

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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

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Dosing