Phar 454: Pk Differences Between Children & Adults

Front 1

challenges in conducting any type of drug research in children

Back 1

-ethics of experimentation

-issues of consent

-small percentage of market (recruitment, "bang for buck")

Front 2

challenges in conducting pharmacokinetic research studies in children

Back 2

-limitations using animal models

-constraint in the number of blood samples that can be collected (newborn baby has ~250mL of blood)

-age categories are not perfect... constantly changing

Front 3

gastric pH changes

Back 3

-greatest changes in the neonatal period

term birth: 6-8 (higher relative pH from reduced acid output and reduced gastric secretions)

day 1-2: 1-3

day ~10: 6-8

then slowly decreases to ~2 by 3 yrs of age

Front 4

oral absorption

Back 4

-drugs must cross GIT membranes to get absorbed

-most drugs are weak acids or weak bases so they are ionized or unionized

-ionized molecules are charged and attract water molecules to form large complexes that cannot easily cross the membranes (therefore drugs are better absorbed if unionized)

-the H-H eqn helps determine the extent to which a drug is ionized at a given pH

acidic env: weak acid unionized: weak base ionized

basic env: weak acid is ionized; weak base unionized

Front 5

gastric emptying

Back 5

-neonates have weaker peristalsis (less muscle)

-prolonged gastric emptying and intestinal transit time in neonates and young infants (adult levels at ~6m)

-differences between formula vs breastfed babies (breast-fed tend to move things through GIT faster)

Front 6

intestinal microflora

Back 6

-in utero, the GIT is sterile but within hrs of birth, microbial colonization begins

-the types of bacteria that will colonize the GIT differ in breastfed vs formula fed babies

-the bioavailability of certain drugs can be influenced by the hydrolysis and the reduction of the drug molecule by microflora (eg clindamycin must be hydrolyzed to active form)

Front 7

IM absorption

Back 7

-decreased muscle mass, erratic blood flow to muscles in neonates

-may have compromised peripheral perfusion (premature neonates)

-variable, unpredictable, unreliable, painful

Front 8

rectal absorption

Back 8

-very vascular area

-can achieve fast systemic concentrations (and effect)

-can be erratic (does not necessarily equal absorption by po route)

-but useful when po not available

Front 9

topical absorption

Back 9

neonates have:

-poorly developed epidermis (especially if premature)

-thinner stratum corneum (esp if premature)

-more hydrated skin than older children/adults

-less hairy

-larger SA

can have significant drug penetration (skin permeability 100-1000x greater in premature neonates than adults; 3-4x greater in full term neonates than adults)

Front 10

BBB

Back 10

immature and more permeable in neonate, especially premature neonates

-increased potential for CNS drug penetration

-increased potential for CNS toxicity

useful in treating meningitis

-abx cross into BBB well

eg: therapy in neonate w meningitis is ampicillin + gentamycin (gent is not used in adults w meningitis b/c does not cross BBB)

Front 11

key determinants of drug distribution

Back 11

water, fat, protein binding

neonate: ECF < ICF < fat

adults: ICF < fat < ECF

eg: gentamycin (hydrophilic)

-will distribute mainly to the ECF

-therefore larger Vd in neonate

Concentration = dose/Vd

the dose required for a neonate to achieve the same concentration as adult is larger (on a mg/kg basis)

Front 12

protein binding

Back 12

albumin (and alpha-1 acid glycoprotein)

-less albumin around (until age 1yr)

-less ability to bind to drugs

eg: phenytoin ~70% bound in neonate, ~90% in adults

-neonates have increased RBC volume and increased RBC breakdown, less albumin, decreased ability to glucuronidate (form water-soluble conjugated bilirubin)

competition w bilirubin for binding to albumin

Front 13

why do we avoid cotrimoxazole in infants < 2mos

Back 13

-competes for binding to albumin

-> displaces bilirubin

-> increases levels of bilirubin

-> can lead to "kernicterus" (can result in severe CNS dysfunction -seizures, death)

Front 14

prothrombin

Back 14

a plasma glycoprotein that gets converted into thrombin during the blood clotting process

Front 15

warfarin

Back 15

-plasma conc. of warfarin, vit K, vit K-dependent proteins, and INR were measured in pre-pubertal, pubertal, and adult pts on warfarin

-similar plasma conc in all groups

-BUT, pre-pubertal pts had significantly lower concentrations of Vitamin K-dependent factors (proteins C and prothrombin 1&2) -higher INRs than the adults studied (more risk of bleeding)

-must consider this increased response to warfarin when estimating warfarin doses in pre-pubertal children

Front 16

antithrombin III

Back 16

a small protein molecule that inactivates enzymes of the coagulation system (ie acts like a "blood thinner")

Front 17

enoxaparin

Back 17

-activates antithrombin III and inhibits anti-Xa so that less thrombin is produced

-the dose for a 1 month old infant is higher than that for a 6 year old child

-partly explained by differences in metabolism/elimination but also antithormbin III levels at birth are less (30-40% of adult levels at birth; 60% of adult levels at 1m)

Front 18

drug metabolism at birth

Back 18

-reduced activity of most metabolizing enzymes: CYP, glucuronidation, conjugation

-liver is big but not very "active"

at 2-4y of age: increased enzyme activity

-doses of many drugs are increased during this time

Front 19

codeine in neonates & young infants

Back 19

-up to 15% metabolized to morphine (active meatbolite) by: CYP2D6, CYP3A4, UGT2B7

-codeine less effective in neonates & young children due to lower metabolism to morphine

-respiratory depression, apnea, and death have occured w the use of codeine as an antitussive in < 1y olds (ability to "deactivate" codeine not fully developed; immature, more permeable BBB leads to higher rates of resp depression w morphine in young infants)

-if mother is prescribed codeine for post-partum pain relief... codeine gets excreted into breastmilk... reaches neonate

Front 20

phase II rxns developed in neonates

Back 20

sulfation: develops in-utero

methylation: well developed in neonates

Front 21

acetaminophen

Back 21

sulfation -> sulfate metabolte

glucuronidation -> glucuronide metabolite

CYP2E1 -> toxic intermediate (NAPQI) -> mercapturic acid (via glutathione)

infants unable to form glucuronidation and CYP2E1 does not develop until ~1y

-therefore infant would need relatively higher dose to get toxicity

Front 22

theophylline

Back 22

baby: used in premature babies w apnea

-methylation to caffeine

++ unchanged in urine

child: rarely used for asthma

-practically no caffeine

-some unchanged in the urine

adult:

-practically no caffeine

-little unchanged in the urine

Front 23

first pass metabolism

Back 23

-liver metabolism after po administration, before reaching systemic circ

-high first-pass = reduced bioavailability

eg: morphine, midazolam, propranolol

ability to metabolize via first-pass is reduced at birth and increases w age

-increased bioavailability of drugs like midazolam

eg. rifampin undergoes first-pass, therefore give less dose to infant

Front 24

renal elimination

Back 24

renal blood flow:

-at birth, < 10% of CO

-by 2-4y, 25% of CO

all renal processes are immature at birth

significant changes in urine output and SCr

each renal process matures at a different stage

-GFR first, then tubular secretion, lastly tubular re-absorption

Front 25

GFR changes

Back 25

at birth GFR is 30-50% of adult levels

-increased by 50% after the 1st week of life due to increased renal blood flow (dosing guidelines may be different between a 4 day old and 9 day old infant)

-reaches adult levels (90-140 mL/min) at ~1y

Front 26

development of renal processes

Back 26

at birth, tubular secretion is 20% of adult levels

-generally, neonates have slower clearance of renally eliminated drugs and require less frequent dosing

-but between 2-24mos of age, GFR and tubular secretion are more mature than tubular re-absorption (for some drugs, this can cause an increase in renal clearance eg. digoxin)

Front 27

Schwartz Eqn

Back 27

to estimate renal fxn (GFR)

GFR (mL/min/1.73m^2) =

(height (cm) x "K")/SCr (umol/L) x 88.4

K = constant based on age and gender

-low birth weight infants (< 2500g) = 0.33

-term neonates & infants = 0.45

-children > 2yrs = 0.41 ("modified schwartz")