NEONATAL PHARMACOLOGY

PAEDIATRIC DIFFERENCES

7/30/2011 5:52:00 AM

-size factor: huge span of weight. -growth and development: maturation of organs -ethics: no one wants to enroll their kids in drug studies -disease spectrum: an infant who suffers from wheeze - prob bronchiolitis. disease spectrum is different. not asthma. lungs not fully developed -Potential for future harm: -Stilboestrol - vaginal adenocarcinoma - lag time for diease to take effect Major PK covariates in children -size -age -organ function -body composition -drug interactions -Pharmacogentics -environmental factors -circadian rhythms DOSE BY AGE? -puberty: endocrine organ changes, metabolize drugs differently -size

CLEARANCE -not a linear relationship with age or weight BODY SIZE IF THE PRIMARY COVARIATE -200x weight difference (e.g. 0.5-100kg -parameters expressed as function of size: lots of common size models -per kg model: doesn't work that well under 40kg -BSA model: overestimates under 20kg -allomtetric model -clin pharmacokinet. 2008; 47(4)231-43 formula remifentayl

-ALLOMETRIC SCALING. it's the same regardless of age -per kilo, there is a change. -clearance mirrors infusion rate -respiratory depression -breathing rate of adult: around 15 -children breathing: about 30/mn. need a .lot more drug to get it down HOW TO DESCRIBE CLEARNACE MATURATION theory: -SHOULD BE CLOSE TO ZERO AT CONCEPTION CL WILL APPEAR DURING DEVELOPMENT IN UTERO -SHOULD reach adult values around age 20 Obversations -slow changes after premature birth whichh age? POST NATAL AGE? -age after birth -does not account for in utero maturation POST MENSTRUAL AGE -on average 2 weeks longer than biological age -age from the woman's last cycle -post conception age; the biological age but not widely recorded Maturation models -linear increase - ok for small age ranges e.g. premature neonates -exponential increase - premature and term OK but not adult values -asymptotic exponential ; term and adult OK but too fast for premature neonates -sigmoid Emax - matches theory and observatio across all ages -also used of enzyme kinetics/ oxygen dissociation MORPHINE CLEARANCE CLEARNACE CHANGES WITH AGE -need allometric model and maturation model to explain it

ORGAN FUNCTION -most kids have normal function -some are diseased -paracetamol is metabolized by UGT1A6(breaks down bilirubin) -can correlate bilirubin concentration with ability to clear paracetamol ALTERED PK -ADME neonatal absorption -thin skin -delayed gastric emtying -altered pH which may affect binding -all their organ systems are immature -drugs absorbed via skin, rectal, PO

RENAL AND METABOLIC MATURATION -emax curve -renal function -all these drugs undergo phase 2 metabolism. conjugation makes it more water soluble. excreted via kidneys -the maturation of the three drugs almost matches renal maturation -propofol metabolism. most are through CYP. those act a lot quicker. ADDDITIONAL CONSIDERTIONS IN OBESITY -incraseted water in lean m ass0 -reduced perfusion fat mass -increased CO -Incrased AAG -lipophilicity -other pathology -egneonate: beckwith wiedemann -child - prader will -teenagers ; diabetes (liver kidneys affected. affect CL

PD effects are altered. when you become obese you get a lot of tissue around head and neck. don't breathe properly when sleep. Obstructive sleep apnea. these individuals are more sensitive to morphine than normal individuals. watch what dose you give not because they're big but because they're sensitive to drugs.

7/30/2011 5:52:00 AM

7/30/2011 5:52:00 AM