Pediatric Pharmacokinetics

true/false:

pediatric deals with minature men and women, with reduced doses and the same class of disease in smaller bodies

FALSE

pediatrics has its own independent range and horizon (infant to 21 year old man)

Challenges Children Pose:

1. _____- based dosing (more calculations)

2. necessity for ________ (commercial products made for adults)

3. absent/limited _______ skills

4. limited capacity to _____ ______ (more limited reserves than adults)

1. weight

2. alterations

3. communication

4. buffer errors

1st day of the moms last menstrual cycle is considered the ______ age

gestational

how long the baby has been alive since birth is considered _____ age

chronological or postnatal age

what is the postmenstrual age of the baby?

gestational age (how long since last period) +

chronological age (how long has it been since birth)

a baby from birth - 1 month is considered to be a _______

neonate

is a 3 month baby (chronological age) a neonate?

NO

considered neonate from birth to ONE month

what is the gestational age of a baby considered to be premature?

what about full term?

premature = less than 37 weeks in womb

full term= 37-42 weeks in womb

an infant is between the ages ____ - _____

1 month to 1 year

to be considered a child you are between the ages of ___-____

1-12 years old

an adolescent falls between the ages of ___-____

13-18

a baby born at 28 weeks gestation is now 21 days old

• what is their gestational age?

• are they premature or full term?

• chronological age?

• postmenstrual age?

• neonate, infant, or child?

• gestational = 28 weeks

• premature because gestational age less than 37 weeeks (full term= 37-42 weeks)

• chronological = 21 days = 3 weeks

• postmestrual = gestational + chronological = 28 weeks + 3 weeks = 31 weeks

• 3 weeks so neonate (birth to 1 month)

most drug absorption takes place in the _______

What happens to gastric emptying and intestinal motility in infants?

What happens to absorption

Does infantile diarrhea increase or decrease transit time?

duodenum

• delayed gastric emptying

• prolonged and irregular peristalsis

delayed and possibly enhanced absorption because of delayed gastric emptying (stays in GI tract for longer able to be absorbed)

decreases transit time (less time to get absorbed)

gastric emptying is delayed in neonates and infants

approximately how long is gastric emptying for neonates vs how long is it for adults?

how long does it take neonates and infants to reach adult time?

neonates + infants = 6-8 HOURS

adults = 20-50 MINUTES

takes neonates 6 to 8 months to reach adult time of 20-50 minutes (easy to remember bc/ their gastric emptying is also 6-8 but hours)

why are neonates at a higher risk of intestinal damage?

poor oxygenation

neonates are subject to intestinal injury and _______ ___________ from ________solutions due to poor oxygenation

necrotizing enterocolitis (NEC)

hypertonic

DONT GIVE BABIES CONCENTRATION SOLUTIONS BECAUSE WATER WILL LEAVE THIER CELLS AND SHRINK/NECROSIS

you want to avoid _____ osmolality drugs and ORAL drugs until full enteral feeding due to the risk of necrotizing enterocolitis in neonates

how can you achieve this?

high

dilute concentrated drugs with milk or water

The American Acedemy of Pediatrics recommends formulas not exceed _____ mOSm/kg HOWEVER

• poly-vi-sol

• acetaminophen suspension

• ferrous sulfate

• calcium glubionate syrup

does this mean patients cannot take these medication?

450

you can still take these medications if you

• split dose

• dilute in water or breast milk

• take after eating (feed)

• take IV dosage

Percutaneous Absorption:

• immature ______ barrier in PReMATURE neonates

  • mature stratum ______ in FULL-TERM neonates

• increase/decrease skin hydration

• increase/decrease BSA: weight

• increased/decreased absorption up to 6 years (vs. adults)

• epidermal

• corneum

• increase

• increase

• increased

NEONATES HAVE INCREASED PERCUTANEOUS ABSORPTION SO BE CAREFUL OF WHAT YOU PUT ON THEIR SKIN SINCE ALOT CAN PENETRATE THROUGH

why are neonates at risk for inadvertent poisoning of topical agents especially premature neonates in the first 2 to 3 weeks of life

they have increased skin hydration and BSA: weight which increases the amount of topical agent that makes it into the blood stream

neonates experienced _________ ___________ when bathed in hexachlorophene (disinfectant) because of their increased absorption through skin

spongiform myelopathy

Why should we avoid giving intramuscular injections to premature neonates and newborns?

• PAINFUL

• babies have insufficient muscle mass, tone, and contraction

• low blood flow

do adults, children, or adults have a higher total body water?

do premature new borns or full term new borns have higher total body water?

large Vd for ___- soluble drugs

infant > younger children > adults

premature (85%) > full term (70%)

water — because they are mostly made up of water

do infants or adults have more total body fat?

do premature babies have more fat than full term?

do infants have to high or low Vd for lipophillic drugs?

adults > infants

full term (15%) > premature (1%)

low Vd because they have less fat

Do infants have a higher Vd for lipophilic or hydrophilic drugs?

hydrophilic bc/ they are mostly made up of water and have less fat then adults

Would adults or infants have a higher volume of distribution of aminoglycosides (ex.gentamicin) ?

does this mean there are higher or lower levels in the blood?

should you give higher or lower doses of benzodiazepines such as lorazepam?

infants bc/ aminoglycosides such as gentamicin are WATER SOLUBLE (hydrophilic)

lower levels in the blood bc/ high Vd

higher doses because for the drug to be effective it needs to have high levels in the blood

do infants or adults have a higher Volume of Distribution for benzodiazepines (ex. lorazepam)

does this mean there are higher or lower levels in the blood?

should you give higher or lower doses of benzodiazepines such as lorazepam?

lower because benzodiazepenes such as lorazepam are FAT soluble (lipophillic) babies do not have much fat

higher level in blood so want to give LOW dose

if too much in blood —> toxic to brain

in general for infants you want to administer

• large doses (mg/kg) for ______ - soluble drugs

• small doses (mg/kg) for ____-soluble drugs

larger - water- high Vd so less in blood (to have effect, want more in blood to reach other areas)

small - lipid - low Vd- a lot in blood, so want less to avoid toxicity

is there more or less plasma binding in neonates and infants?

is there an increase or decrease in the affinity and binding capacity of albumin binding sites for infants and neonates?

less plasma binding so more available to reach tissues

decrease in affinity and binding to albumin

true/false: highly protein bound drugs have higher free fraction in neonates

true

less of the drug is bound to proteins due to decreased affinity to albumin

true/false: there is a risk of displacing bilirubin from albumin in neonates and infants

true

why should you avoid administering drugs to neonates that will compete for albumin sites?

there is already so little albumin so if you are giving drugs that compete for albumin, then there is a toxicity risk for both drugs involve as they will not have a place to bind in blood keeping them away from tissues

phenytoin:

what perecentage of phenytoin is free in adults?

what percentage of phenytoin is free in neonates?

why is this the case?

10% free adults (90% protein bound)

20% free in neonates (80% protein bound)

there is less albumin production by the liver in neonates

Phenytoin therapeutic range:

10-20 mcg/mL

neonate: 6-15 mcg/mL

therapeutic free level: 1-2 mcg/mL

why is the therapeutic range for neonates lower?

therapeutic range for neonates is lower because they have more drug that is unbound bc/ of their lack of albumin

takes less drug to get to toxic levels for neonates

Phase 1 Reaction:

• What are the three major phase 1 reactions?

• Do neonates or adults have more P450 enzymes?

• How long does it take babies to reach adult values of P450 enzymes?

• Do all of the P450s mature at the same time?

• oxidation, reduction, hydrolysis

• Adults have more

• 6 months

• no all the subfamilies have different dates of maturity

at what age do children have a higher metabolism than adults?

ages 2-3

Age-related phenytoin dosing (mg/kg/day):

Would you prescribe higher doses of phenytoin to adults or neonates?

Which age range would you prescribe the highest dose of phenytoin?

higher dose to adults bc/ neonates have low albumin levels and can reach toxic levels quick

highest dose prescribed to 6 month to 3 year old (8-10) because they have higher metabolism than adults at ages 1- 2

Metabolism Phase II Reactions:

When do babies reach adult levels of glucuronidation?

How do they compensate for lower levels of glucuronidation as neonates?

18-34 months up to 48 months

Sulfation is developed at birth

which phase 2 metabolic process is fully developed at birth?

sulfation

recommended dosing schedules in children are based on _______-_____ estimates of CLEARANCE

Careful monitoring of

• pediatric dosing

• serum concentrations

• potential toxicity

  should be emphasized

population based

does glomerular filtration or secretion mature quickly after birth, which proceeds more slower?

glomerular filtration quick

secretion is slower

when do babies reach adult values of glomerular filtration and tubular functions?

glomerular filtration - 6-12 months

tubular functions - 6-8 months

why should you give lower doses of renally cleared drugs during the 1st week of life?

renal filtration does not reach adult levels until 6-12 months

which equation is best used to estimate creatinine clearance?

Modified Schwartz equation (IDMS-traceable method):

CrCl (mL/min/1.73 m2) =

0.413 x height (cm) / Scr (mg/dL)

The modified Schwartz equation is also called the ________ method

The Schwartz method (outdated) is also called the ______ _______ - based method

IDMS- traceable

alkaline picrate

is the following the modified schwartz equation or schwartz equation?

CrCl (mL//min/1.73m2) =

k x height (cm) / Scr (mg/dL)

shwartz (alkaline picrate)

Special Consideration in Children

• _____-specific dosing regimens

• drug ________

• ______ sampling

• interpretation of drug levels

• age

• delivery

• blood

true/false:

There are NO standard dosing for pediatric patients

true

Pediatric References:

1. Pediatric & Neonatal Dosage Handbook (_______)

2. Neofax ( _________)

3. ____ Book (AAP) — infectious diseases

4. ______ Handbook (NOT THE BEST TO USE) — pediatric house officers’ manual

5. Teddy Bear Book, Pediatric Injectable Drugs

4. Pediatric Medication Education Text

5. Pediatric Drug Formulations (extemporaneous formulations)

6. Facts and Comparisons

7. AHFS Drug Information

1. Lexidrug

2. micromedex

3. Red

4. Harriet Lane

which three resources can be found through Rutgers libraries?

1. neofax (micromedex)

2. pediatric and neonatal (lexidrug)

3. red book (AAP)

what 4 factors should you consider when making a dose?

1. age

2. diagnosis

3. concurrent disease states

4. organ function

what units are used pediatric medications?

1. mg/kg/dose

2. mg/kg/day

3. mg/m2/day

when a patient’s calculated dose exceeds the adult dose the pediatric patient should be dosed according to _____ medication guidelines

KNOW WHEN TO SAY WHEN !

adult

Drug Delivery

• ____ form

• route of _______

• delivery ________

• method of _________

• dosage

• administration

• system

• administration

what is the recomended dosage form for pediatric patients?

at what age can patients begin to swallow pills?

oral (specifically CHEWABLE)

5-6

why should you be aware of preservatives when administering oral medications to pediatric patients?

certain preservatives cannot be metabolized such as benzyl alcohol which is able to turn into benzaldehyde with alcohol dehydrogenase and benzoic acid with aldehyde dehydrogenase BUT CANNOT turn benzoic acid into hippuric acid leading to acidosis due to lack of amino acid conjugation with glycine

what are 4 ways to modify commercially available products to be more suitable for pediatric patients?

1. dilute liquids

2. split tablets

3. turn injectables into oral forms

4. crush tablets or empty tablets and mix w/ beverages or soft foods or enteral feeding formulars or

you should never crush _____ release tablets and always watch for medication/enteral nutrition interactions

sustained

what complications may arise due to the frequent small volumes of IV formulations for pediatric patients?

• delayed drug delivery

• underdosing

• patients susceptible to fluid overload

How can you overcome delayed drug delivery with IV formulations?

you can flush the line with minimal fluid to make sure the drug reaches the end of the long tube

Baby Boy Brown is a 35 week GA neonate (DOL2) being treated with ampicillin and gentamicin for sepsis.

His nurse draws the gentamicin peak and trough levels around his 4/14 13:00 dose (dose #3)

PEAK: 2.1 mcg/mL (drawn 4/14 14:00)

TROUGH: 1.8 mcg/mL (drawn 4/14 12:30)

tubing issues

peak which is the level right after administration should be significantly larger than trough (around the end)

the peak should have been MUCH larger 2.1 than 1.8

syringe pumps with _______ IV tubing is preffered for pediatric patients

microbore

how long after the flush should you experience peak?

Administer the drug and then the flush

peak levels should be reached 30 minutes after end of flush

a baby in the NICU is going to be treated for 10 days with gentamicin and a peak and trough level are ordered. The bedside nurse asks you what time she should draw the peak and trough levels

3rd dose (2mg) is due today at 1400. She will administer the dose over 30 minutes, followed by a 30 minute flush.

check trough at 30 minutes before the new dose

check peak 30 minutes after you administer flush

Mary is a 10 year old girl admitted with fever and neutropenia. She is started on cefapime and tobramycin.

She is clinically stable and does not have any obvious sources of infection on physical exam

Renal function is normal

Do we need to order tobramycin level at this time?

NO

if renal function seems normal and there’s no sources of infection, then we can assume her tobramycin levels are normal and don’t have to check

Mary grows Pseudonomas Aerguinosa from her peripheral and central blood cultures. She is heterodynamically stable.

ID recommends continuing cefepime and tobramycin for 14 days.

She has recieved 3 doses of tobramycin to date

(4/14: 04:00, 4/14 12:00. 4/14 20:00) every 8 hours next dose is due 4/15 @ 4:00

If and when should we draw tobramycin levels

we should draw tobramycin levels

trough: 3:30 AM

peak: 5:00 AM

BUT BABY WILL BE ASLEEP SO CHECK AFTER

12:00

trough: 11:30

peak: 13:00

true/false: treat the patient not the level

true

interpretations of levels:

• exact ___ of sampling

• exact time of all relevant _____

• administration and sampling _____

• dosing regimen

  • dose, frequency, duration, dosage form, route

• Patient Characteristics

• ___________ medications

• _____ for medication and level

• therapeutic _______

• time

• doses

• method

• concurrent

• indication

• range

what are the essential parts of the dosing regimen?

1. dose

2. frequency

3. duration

4. dosage form

5. route

which patient characteristics are relevant is dosing?

1. age

2. weight

3. diagnoses

4. dosage form

5. route