Peds

Question 1

What about growth and development makes peds a special patient poputlation? (3)

Answer 1

1. Heterogenous population
2. Maturation is a variable process
3. Pathological considerations

Question 2

In terms of available PK/PD information, what makes peds a special population? (3)

Answer 2

1. Clinical studies use healthy adult subjects
2. Exclusion criteria
3. Therapeutic orphan

Question 3

Describe the growth of an infant for the first 2 weeks after birth

Answer 3

5-10% weight loss from birth weight

Question 4

Describe the growth of an infant from 4-6 months

Answer 4

Infant should double birth weight

Question 5

Describe the growth of an infant from 1-5 years

Answer 5

Toddler gains about 2.2kg/year

Question 6

What is dose normalization?

Answer 6

Need to consider changes in body surface area/mass

Question 7

What is developmental pharmacology? (4)

Answer 7

1. PK and PD of drugs and the clinical characteristics of neonatal and pediatric populations
2. How human growth and development change PK/PD relationship in each unique patient
3. Accurately determine safe and effective doses for pediatric patients
4. Variability in rates of development

Question 8

What are the 2 goals of developmental pharmacology?

Answer 8

1. Understand the impact of maturation on drug’s ADME (PK)
2. Describe the PD: knowing the concentration of drugs and the expected response

Question 9

What are the general effects on ADME as children age? (3)

Answer 9

1. Pharmacokinetic changes
   - Anatomical and physiologcal changes
   - Age-related changes in organ function are responsible for changes in PK (kidney, liver)
2. Rate of maturation of ADME processes is most in the first 2 years of life
3. Generally slower in neonatal period, increasing into childhood

Question 10

What are some developmental maturation factors affecting rate and extent of GIT absorption? (7)

Answer 10

1. GIT surface area
2. GIT perfusion
3. Gastric pH
4. Gastric emptying and intestinal motility
5. Pancreatic exocrine and biliary function
6. Bile salts
7. Enzyme activity and first-pass effects

Question 11

What is important to know about gastric pH at birth and as the kid ages? (3)

Answer 11

1. Important for drug stability, dissolution, and ionization
2. Birth: neutral gastric pH
3. Progressive decrease over several weeks to years
   (e.g., oral penicillin)

Question 12

What to know about gastric emptying and intestinal motility as kids age? (3)

Answer 12

1. Affects intestinal drug absorption
2. Limited understanding of the effect of age
   - Changes in Tmax in younger ages (? delayed onset of meds)
3. Comparable to adult values and function by 2 years

Question 13

What to know about intestinal transporters and enzymes in kids? (2)

Answer 13

1. Influx and efflux transporters (P-gp)
2. CYP3A4 maturation and first-pass effect

Question 14

What food considerations to be aware of in neonates and infants? (2)

Answer 14

1. Neonates and infants are fed more often
2. Types of food: breastmilk vs. formula vs. solids

Question 15

Major factors governing distribution include: (3 - not even peds, just general)

Answer 15

1. Body composition
2. Plasma protein binding and tissue binding
3. Hemodynamic factors
   - Tissue perfusion and cardiac output
   - Vd influences loading dose. Hence, larger Vd relative to body weight will require larger mg/kg doses

Question 16

Should know the body water composition for the following ages:
1. Preterm neonate
2. Term neonate
3. 1-2 years
4. >2 years

Answer 16

1. 80-90%
2. 70%
3. 60%
4. Stabilization

Question 17

How does % of lipophilic tissue change with age? (neonate until adolescence roughly)

Answer 17

It peaks at the end of infancy and decreases until adolescence basically.

Question 18

Why does body water composition even matter? To help, think about a drug that has a relatively low Vd (<1 L/kg) (3)

Answer 18

1. Vancomycin or enoxaparin, for example
2. In an average adult we have predictable kinetics
3. In neonates, they are large water containers
   - Dilutional –> higher doses of drug likely required to produce therapeutic effect
   - Unpredictable

Question 19

What to know about protein binding in peds? (3)

Answer 19

1. Lower concentration of plasma binding proteins
   - Albumin, alpha-1 glycoprotein, plasma globulins
2. Binding affinity
3. Presence of pathophysiologic conditions or endogenous compounds (bilirubin, free fatty acids)

Question 20

Why does protein binding even matter? (3)

Answer 20

1. Free fraction of drug exerts pharmacological effect
2. Increases free drug: affect pharmacological effect and clearance
3. Highly bound drugs and narrow therapeutic index

Question 21

How do the following states affect distribution?
1. Obesity
2. Malnutrition
3. Sepsis

Answer 21

1. Lipid compartment
2. Albumin deficiency
3. Plasma compartment

Question 22

How is hepatic blood flow different at birth? (2)

Answer 22

1. At birth: hepatic blood flow and oxygen tension change rapidly due to:
   - Umbilical vein blood supply terminated
   - Portal venous and hepatic arterial blood increase with closure of the patent ductus venosus
2. Hepatic blood flow difficult to measure
   - Unlikely to affect elimination capacity in neonates

Question 23

How does splanchnic blood flow change with age?

Answer 23

Increases rapidly postnatally to support mucosal growth and enteral nutrition

Question 24

How does renal blood flow change starting from birth? (4)

Answer 24

1. Renal perfusion at birth <20% renal perfusion adult
2. Increased cardiac output (as child ages)
3. Decreased renal vascular resistance
4. Increased GFR

Question 25

How does organ size play a role in elimination? (3)

Answer 25

1. Elimination capacity depends on developmental changes in:
   - Function
   - Relative size
2. Higher ratio of organ/body mass in the neonate and infant relative to adult
3. Age-dependent Cls may reflect liver size/body weight difference (not Clint/g liver)

Question 26

How are enzymes different in peds? (2)

Answer 26

1. Maturational differences
   - Slower in infancy
   - CYP development - drug-drug interactions
2. Sulfation and glucuronidation

Question 27

What are the general patterns of hepatic enzyme ontogeny? (2)

Answer 27

1. Developmental Switches: change in predominant metabolic pathway(s) with maturation
   - E.g., CYP3A7 (predominantly in neonates) vs. CYP3A4 (predominantly in adults)
   - Alteration in metabolite profiles, toxicity risk, efficiency of elimination
2. Variation in enzymes
   - Vary in number through developmental stages
   - May be different between children of the same age

Question 28

Describe GFR and tubular secretion in peds

Answer 28

1. GFR:
   - Full-term newborn: 10-20 mL/min/m^2
   - Rapid increase during the first weeks of life –> adult values by 3-5 months
   - Schwartz equation
2. Tubular secretion and reabsorption are much slower

Question 29

Describe the maturation of renal clearance mechanisms (2)

Answer 29

Developmetal changes in kidney anatomy
1. Nephrogenesis complete at 36 weeks
- Thereafter, increases in renal mass due to increase in renal tubular growth
2. Children have the fastest rate of increasing glomerular and tubular cell size

Question 30

Describe the developmental changes in glomerular filtration (3 - premature infants, 6 months age, early childhood)

Answer 30

1. Premature infants exhibit reduced GFR
   - Slower pattern of GFR development in the first 1-2 weeks PNA
2. By 6 months of age, GFR has approached adult levels
3. Early childhood to early adolescence age GFR exceeds adult levels
   - Maximum relative kidney weight

Question 31

Discuss renal tubular elimination in peds (3)

Answer 31

1. Immature renal tubules compromises passive and active reabsorption and excretion processes
   - 20-30% adult value at birth
   - Increases slowly and variably
2. Reach adult values at 1-5 years of age
3. Transporters: little information about development