Buxton: Pharmacokinetic Considerations in Peds

Question 1

What is unique about pharm in kids?

Answer 1

continuous development from embryo to adolescence

Question 2

Are children miniature adults?

Answer 2

No, dosing based on a rule or scaling (by body weight or surface area) not always predictable

Question 3

What is Clark’s rule?

Answer 3

Weight (lbs)/150 x adult dose = approximate child’s dose

Question 4

What is Young’s rule?

Answer 4

Age (yrs)/Age +12 x adult dose = approximate child’s dose

Question 5

Only (blank)% of approved drugs have pediatric labeling. In the meantime, the FDA is encouraging pediatric studies.

Answer 5

30%

Question 6

Young children are “moving targets,” because they undergo many changes over the course of their growth. What are some examples?

Answer 6

Body composition 
Organ function
Drug metabolizing enzymes
Unique metabolic pathways
Renal function
Receptor response
Unique disorders

Question 7

What are some gastric absorption differences in kids vs adults?

Answer 7

Gastric acid - approaches adult values ~ 3 mo in full-term infants.
Digestive enzymes including pancreatic enzymes are low in newborns.
Gastric emptying is delayed and unpredictable in newborns
GI motility is low in newborns; may be increased in children

Question 8

What are some differences in skin absorption to be aware of in premature infants?

Answer 8

Premature infant has thin skin - a significantly less effective skin barrier to absorption of drugs and toxins

Question 9

What is one concern with using intramuscular drugs in children?

Answer 9

dispersion driven by muscle contraction is low in neonates
low skeletal muscle blood flow in neonates
these can be very painful, can cause nerve damage, abscess, necrosis, fibrosis

Question 10

Other sites of administration of drugs for infants?

Answer 10

rectal
pulmonary
unintentional: breast milk & placenta

Question 11

How does the extracellular and total body water space compare in neonates & young infants vs adults?

Answer 11

Larger extracellular and total-body water spaces in neonate and young infants

Question 12

How do plasma proteins compare in preemies and neonates? Which is most important to consider?

Answer 12

they are low, so lead to increased free fraction;

most important in displacement of bilirubin from albumin –> kernicterus

Question 13

How do tissue transporters differ in infants?

Answer 13

reduced expression of P-glycoprotein ATP-binding cassette family of transporters..

Question 14

What happens to drug metabolizing enzymes in the very young?

Answer 14

they have low activity

**be careful with drugs that have a wider therapeutic index!

Question 15

What is the major isoform of drug-metabolizing enzymes in the infant?

Answer 15

CYP3A7

**w/i hours after birth, other isoforms appear

Question 16

Give an example of the differences in half-life of a drug in infants vs 1 wk old full term infant

Answer 16

Phenytoin T1/2 in preemies is 75hrs vs 20hrs in 1 wk old full term infant

Question 17

What are the phase 1 reactions?

Answer 17

oxidation/reduction/hydrolysis

Question 18

What are the phase 2 reactions?

Answer 18

conjugation reactions

Question 19

This conjugation enzyme is decreased in newborns & young children compared to adolescents & adults

Answer 19

glucouronosyl transferase

Question 20

Clearance of most agents more efficient in (blank) than adults (relative to bodyweight)

Answer 20

prepubescent children

Question 21

Premature infants have decreases in almost all phase 1 enzymes, except for this one!

Answer 21

CYP3A7

Question 22

Premature infants have decreased (blank) of phase 2 enzymes

Answer 22

activity

Question 23

What happens to GFR in children?

Answer 23

progressively increases until about age 6

Question 24

Estimation of (blank) may be necessary for determining dose regimen for drugs with extensive renal clearance

Answer 24

renal function

Question 25

This drug can actually alter renal blood flow

Answer 25

indomethacin

Question 26

What are some things to think about when deciding whether to use a drug in a child or infant?

Answer 26

Has there been documented efficacy for the medication for the disorder in newborn or older infants/children.
Has the safety been established for pediatric population?
Has the pathway of drug clearance been established in children/infants?
Is that pathway established in the child/infant you are treating (based on maturity or physical state)?
Is there reason to believe that pathway may be compromised in the specific child/infant (genetics, disease state, concomitant therapy)?
Have the pharmacokinetics been established in similarly aged children?

Question 27

The very small doses required in the most immature patients and the immature clearance pathways leave very little (blank)

Answer 27

margin of error

Question 28

What is retrolental fibroplasia?

Answer 28

retinopathy due to high oxygen (increased blood vessel proliferation on the retina)

Question 29

This anti-infective can be toxic to infants but was used to eliminate Staph infection in nurseries

Answer 29

Chloramphenicol

Question 30

This was another anti-infective that went awry in nurseries

Answer 30

novobiocin

Question 31

This compound was used to disinfect diapers, but was toxic to the children

Answer 31

pentachlorophenate

Question 32

These caused magnesium toxicity in nurseries

Answer 32

epsom salt enemas

Question 33

Bottom line: there are many cases of pediatric toxicology

Answer 33

Yes

Question 34

How often do prescribing errors occur in the pediatric ER?

Answer 34

10% of charts have prescribing errors

Question 35

Another type of error that occurs often in peds

Answer 35

sedation errors

Question 36

As few as (blank)% of parents correctly administer proper dose of acetaminophen to their child
Even when parents provided with correct dosing information and child’s weight, correct dose given 40% of the time

Answer 36

30%

Question 37

Should aspirin be given to children?

Answer 37

NEVER - until about age 15

Question 38

T/F: Significantly fewer errors associated with simplified color-coded information sheet and color-coded dosing syringe

Answer 38

True

Question 39

Overdosing & underdosing is very common in pediatrics

Answer 39

Yep

Question 40

What are the challenges in pediatric prescribing?

Answer 40

1. Pediatric prescribing is complex - need to get an accurate weight, convert weight to kg, make calculations, etc
2. Off-label medication use is common - increase risk of adverse drug events
3. Lack of standardization of recommended doses - they differ depending on your source
4. Lack of guidelines regarding use of adult dosing regimens - there’s no standard for when to switch from weight-based dosing to daily dosing

Question 41

Which children are at the highest risk for prescribing errors?

Answer 41

young children
children who have not been seen in clinic
multiple medications at one time
“prn” medications (analgesics, asthma meds)

Question 42

What is the major problem with pediatric prescribing?

Answer 42

Not enough is being done by big Pharma to study drug dosing in the pediatric population thought this is slowly improving.

Question 43

Will computerized physician ordering entries reduce medication dosing erros in children?

Answer 43

Electronic prescribing is a potentially successful strategy but NOT without pediatric decision support
Evidence in inpatient settings that CPOE reduces medication dosing errors
Complexity of pediatric prescribing leads to complexity in designing electronic systems