developmental pharmacology (pediatrics)

dose standardization for pediatrics

• standardize doses either as amount per kg or per BSA

scheduled dosing regimen

• amount/kg/day divided q 4,6,8,12 hr

intermittent basis or prn

• amount/kg/dose given q 4,6,8 hr PRN

dosing reference sources for pediatrics

• pediatric dosage handbook form Lexi-Comps reference library

• primary literature

age specific dosing

• children are NOT miniatrue adults

• humans growth is NOT linear process

• age associated changes in body composition and organ function are dynamic during the first decade of lide

pharmacokinetics

• relationship between dose and concentration

• ADME

pediatric absorption gastrointestinal tract

• ph: elevated intragastric pH during neonatal period

• gastric emptying and intestinal motility

  • matures by 4 months

• intestinal drug metabolizing enzymes and efflux transporters

percutaneous absorption pediatrics

• stratum corneum

• cutaneous perfusion and hydration of the epidermis

• the ratio of TBSA: BM in infants > adults

  • corticosteroids, antihistmaines, antispetics, propylene glycol

• full term and hydrated → good absorption

• pre mature→ very thin skin, too high absorption

distribution in pediatrics

• changing the relative sizes of drug distribution compartments contributes to the dynamic nature of pediatric dosing requirements

• babies have larger tanks → more water

• directly related to gestational age

• determines how much drug

developmental changes in body composistion

• premature infants

  • TBW 85-90%

  • Fat 1-5%

  • muscle-skeletal 20%

  • albumin 2.5-3.5

• neonates

  • TBW 70-80%

  • Fat 15-20%

  • muscle-skeletal 25%

  • albumin 3-4

• adults

  • TBW 50-60%

  • Fat 15%

  • muscle-skeletal 50%

  • albumin 4-5

premature infants

• TBW 85-90%

• Fat 1-5%

• muscle-skeletal 20%

• albumin 2.5-3.5

neonates

• TBW 70-80%

• Fat 15-20%

• muscle-skeletal 25%

• albumin 3-4

adults

• TBW 50-60%

• Fat 15%

• muscle-skeletal 50%

• albumin 4-5

metabolism in pediatrics

• primarily occurs in the liver

• can also occur in: blood, lung, GI tract, kidney

• in general, neonates have decreased biotransformation, which increases from 1 to 5 years of life followed by a decrease from puberty throughout life

phenobarbital

• metbaolism increases as a function of PNA

theophylline

• metabolism

• N methylation to caffeine in neonate

• N demythlation - normal adult pathway

• 4-5 months theophylline clearance reaches adult values

• 7-9 months the adult metabolic pattern is attained

• younger children have increased activity

elimination in pediatrics

• determines interval

• different rate of maturation for each renal function → filtration, reabsorption, secretion

• at birth kidneys receive only 5-6% of CO at birth compared to 15-25% in adults

6-8 months

• age where kidneys begin statting to be more normal (adult like)

• GFR 110.7

• 60 tubular secretion

aminoglycosides

• neonates have reduced CL due to decreased renal blood flow, GFR, and tubular function (typically extend interval to q12, q24, q48)

penicillin

• adults 90% tubular secretion whereas neonates GFR is the major pathway of elimination

aminoglycoside dosing for pediatrics

• higher dose for longer interval

CYP2D6 pharmacogenomics in kids

• atomoxetine

• codeine

• tramadol

• all have black box warnings

atomoxetine

• dose should be decreased to prevent toxicity in children who have decreased CYP2D6 activity (poor metabolizers)

tramadol

• black box warning due to risk of slowed or difficult breathing especially in ultra-rapid metabolizers for tonsillectomy/adenoidectomy

• in ultra rapid metabolizers an increased amount of O-desmethyltramadol, an opioid metabolite of tramadol, is formed resulting in the adverse effect

codeine

• like tramadol in ultra-rapid metabolizers

• avoid tylenol #3