Introduction to Pediatric Pharmacotherapy

What age group is considered to be pediatric ?

0-18 y

*age is decided by organ development which will determine the dosage of a medication

Neonate age range

0- 1 month of age

Infant age range

1 month to 1 year

Child age range

1 to 12 years

Adolescent

12- 16 years

Full term neonate

born between 37-42 weeks (average is 40 weeks)

Premature neonate

born before 37 weeks of gestation

Gestational age

conception to date of birth

(how many weeks old the baby is)

Postconceptual age

GA +PNA

Corrected Age

real age

(full term (40) - gestational age)

When should sulfonamides not be used in children

before 3 months

when should tetracyclines not be used

before 8 years of age

When should fluoroqunolones not be used

before the age of 18

what percent of drugs are marketed in the used do not carry FDA- labeled indications for pediatric use

50%

What is the reason for lack of well-designed trials in children

logistical, technical, finacial, ethical

*most parents do not want to enroll their child in trials

Fundamentals : normal vital signs

Children HR is higher 60-80 bpm

Children BP - lower 70/30

SrCr and albumin is lower in younger infants - clearance is also different compared to adults (kidney function - protein in blood that drug binds to)

neonate HR higher - 150 bpm

Main oral absorption factors

1. Gastic duodenal pH

2. Gastric emptying time

3. Active transporters

What is the gastric pH of neonates at birth

6-8

Gastric pH of full-term neonates

neutral or reach adult pH, 1-3, within 24 hours

Preterm neonates gastric pH

more basic adult pH delayed up yo two years

What does pH affect

ionization of drugs impacting dissolution and absorption

Effect of delayed achievement of adult gasttic pH in premature neonates

• higher serum levels expected

What is the pancreatic enzyme necessary for enzyme activity

alpha amylase

What is the pancreatic enzyme activity in neonates

reduced concentrations of bile acids and activity of alpha amylase

What is the result of reduced concentrations of bile acids and activity of

alpha amylase ?

Reduced absorption of lipid-soluble drugs

ex.) chloramphenicol reduced ability to cleave prodrug esters and inability to liberate active drug, resulting in excessive levels of parent drug

How can IM absorption be altered in premature infants

difference in relative muscle mass

poor perfusion to various muscles

peripheral vasomotor instability

insufficient muscular contractions

When is IM absorption used

when child is unable to take medication orally

IV access is lost

*not the preferred route on administration

Concerns of IM absorption

• erratic absorption of some drugs

• painful

• unpredictable absorption ex. phenobarbital absorbed quickly, diazepam is delayed

Transdermal drug delivery

stratum corneum is thinner in younger infants

greater cutaneous perfusion/ hydration of epidermis

greater BSA:body weight ratio in infants

*infants have higher fluid concentration that is why absorption is better

Greater systemic exposure (absorption) in premature infants

Rectal transmucosal absorption

• in critically ill children very unpredictable and not recommended

• difficult to keep suppositions in

Solutions or fast melts are preferred

Drug distribution (passive diffusion along concentration gradients) is influenced by which patient factors

body composition

protein binding

Body composition

impacts drug dose and serum levels in children

*larger ECF need more drug because you have a larger volume of distribution

as you get older the amount of water in your body decreases

greater Vd in neonates = higher dose than adult

Water soluble drug = higher dose per kg

Lipophilic drug= lower dose per kg

increased concentration of free unbound drug leads to what

greater pharmacological effect

*more unbound drug= more effect

what are clinical implications of drugs that are highly protein bound

has a narrow therapeutic index

Who is affected by increased or decreased plasma protein binding

neonate/infants

any patient with liver or renal failure

What is the effect of reduced binding capacity

higher free concentrations of certain medications

due to decreased PPB there is and increase in Vd and higher loading doses

infants have less of the drug bound, so more is free

Why do some neonates have higher bilirubin levels

RBC destruction/impaired glucuronidation

What happens when bilirubin binds to albumin and competes with highly PPB drugs

1.  displacement of highly PPB drugs from PPB binding sites, increasing free drug concentrations and pharmacological effect

AND / OR

2. Displacing bilirubin, which enters the brain and causes kernicterus (brain damage, hearing loss)

how long does it take the glucuronidation pathway to be fully developed

1 year

sulfation pathway well-developed in infants

what are higher serum Cp morphine needed to achieve efficacy in premature neonates when compared to adults

limited capacity to metabolized morphine to its M6G

Cytochrome P450

34A

*most abundant enzyme in the liver and intestine

• 50% of all drugs

• present by very low activity at birth

• 30-40% of adult activity by 1 month

• maturations 12 months

• examples - midazolam, carbamazepine, calcium channel blockers, sildenafil, cisapride