Download Pediatric Pharmacology

Pharmacology: Pediatrics (Valentine)
TERMINOLOGY:
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Premature Infant: a child born before 36 weeks gestational age

Neonate: a child less than 30 days old
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Infant: a child who is in their first year of life
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Toddler: children 2-3 years of age
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Child: a person less than 8 years of age (after this age, they are fairly similar to adults in pharmacological terms)
ABSORPTION:

General:
Anatomical and physiological differences between infants and adults results in difference in the rate and extent
of drug absorption in infants
Absorption refers to the translocation of the compound from site of administration to bloodstream
No age related differences in IV absorption (complete absorption of agents given by this method)

Cutaneous Absorption:
Enhanced during infancy: due to development of cutaneous layers (not fully developed and thinner), level of
hydration and cutaneous perfusion of the epidermis in children
o Children/infants also have a higher proportion of body surface area to mass
Premature infants: enhanced cutaneous absorption may be even greater due to the fact that barrier dysfunction
has a linear relationship with prematurity (ie. more premature an infant it is, the less fully developed the barrier
function of the integument)

Intramuscular Absorption:
Not a preferred route in pediatrics: due to pain (but a good alternative in patients with poor IV access)
Factors affecting IM absorption:
o Nature of the compound (ie. medication, vaccine etc.)

Must have enough lipophilicity to be absorbed through the tissue into the capillaries

Must also have enough water solubility at physiological pH to prevent precipitation at
injection site
o Patient related factors

Patient has to have adequate blood flow to the muscle bed for absorption to take place

Muscle activity is also important in rate of absorption (inactive/immobile patients can have
reduced absorption compared to active patients)

GI Absorption:
Oral administration: most common way to dispense medication to children
Important considerations in neonatal/infant population:
o Changes in gastric pH (higher in neonates than adults- neutral at the time of birth and then has a
delayed drop over several months)

pH of 4-7 for first few weeks of life; pH of 3 by 4 months of age

Result:
 Acid-labile medications will be readily absorbed (ie. penicillin G)
 Weak acids may need LARGER oral doses in neonates to reach therapeutic levels
(ie. phenobarbital)
o Changes in gastric emptying and intestinal motility

Gastric emptying increased in the first few days-weeks of life

Intestinal motility improves throughout infancy with more efficient propulsion/contractions,
allowing for more augmented absorption
o Differences in bile salt pool
o Differences in intestinal surface area and integrity

GI surface area is thought to be smaller in infants
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GI integrity is intact in a full term child
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GI muscosa of premature infant may provide less of an absorptive barrier
Rectal Administration:
o Use: may not be as reliable as the oral route

Antipyretics (ie. acetaminophen)

Anticonvulsants (benzodiazepines have lipophilicity and pKa that is good for absorption from
the rectum; often prescribed as a home rescue med for children with epilepsy)

Pediatric Preparations:
Children below a certain age cannot swallow pills or tablets well (many compounded into liquid form)
o
o
Solution: medication dissolved throughout the liquid
Suspension: medication particles suspended in the liquid and are subject to gravity (will sink to the
bottom; need to SHAKE BEFORE USE*)

Ingesting a suspension (which has a larger surface area:volume ratio) can result in a more
rapid transmucosal transport and a shorter lag to peak serum concentration compared to a
tablet
DISTRIBUTION:

General:
Distribution of most substances in the body depends on:
o Compartment sizes
o Protein binding
o Membrane permeability
Volume of distribution is the most important PK parameter affecting drug distribution
o Represents apparent space in the body available to contain a drug
o Also reflects the amount of a drug in the body to its concentration in a biological fluid (plasma)
o For an given drug, the Vd will differ from patient to patient based on protein binding AND body
composition (significant age related differences, mostly due to alterations in total body water)

Total Body Water:
Neonates/Infants:
o Greater total body water than adults

At term, TBW is 75% of body weight

4-6 months of age, TBW is 60% (remains constant until adulthood)

Adulthood, TBW is 50-60%
o Larger extracellular compartment
Dose Adjustment: if you do not dose-adjust for the changes in TBW and compartmentalization, water-soluble
drugs (even if administered in proper weight based fashion) will have LOWER plasma levels (due to larger Vd)
o To achieve comparable drug concentrations that distribute to total body water, higher doses per kg
of body weight must be given to infants and children in comparison with adults

Protein Binding:
Some drugs bind plasma proteins (bound drug typically not pharmacologically active)
o Commonly bound proteins include albumin and α1-acid glycoprotein
Degree of protein binding depends on:
o Available concentration of protein
o Avidity of protein for certain medications
o Certain pathophysiological conditions that affect protein binding (ie. acid-base state)
Neonates/Infants:
o DECREASED protein binding
o Drugs that are highly protein bound (ie. phenytoin) will therefore have their free (and active)
concentrations increased
o Therapeutic drug monitoring of serum levels of bound and unbound drug is important

Fat Composition:
Distribution of fat-soluble drugs is dependent on fat composition of the body and total body water
Infants:
o By 2-3 months of age they have higher body fat and lower amount of lean muscle mass than adults
o Therefore, drugs with high fat-solubility will have a higher Vd
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Important Take Home:
Infants have a higher percentage of body fat AND total body water
Therefore, the Vd for both fat- and water-soluble drugs is HIGHER compared to adults
CLEARANCE:

General:
Clearance of a medication relates to the elimination of the active drug from the body
Clearance is a function of metabolism of the active compound into an inactive form AND/OR excretion of the
drug from the body
Several age related differences that need to be accounted for by changes in the drug dosing amount and interval
to prevent toxicity in children
o Example of Toxicity: gray-baby syndrome with chloramphenicol

Metabolism:
Liver plays an important role via biotransformation of active compound
o Phase I (oxidation, reduction, hydrolysis and hydroxylation; most often CYP450 system)

CYP Activity: reaches adult levels by 1 year of age (in utero, only 30-60% of adult levels)
 Therefore, hepatic metabolism of most drugs is decreased in neonates and infants
 However, metabolism of certain drugs can be higher in infants and children than in
adults
o Example: carbamazepine (clearance is higher in children resulting in
higher dose per body weight and shorter interval between doses for
children)
o Phase II (conjugation reactions that increase water solubility and renal/biliary excretion of the drugs)

Sulfation: plays an important role in hepatic metabolism/drug clearance in the newborn
since other conjugation pathways are not well developed until well into post-natal period
 Significant sulfortransferase activity is expressed in fetus and infant

Glucouronidation: most common conjugation pathway because glucuronic acid can combine
with a large variety of molecular groups
 Catalyzed by UDP-glucuronosyl transferase, which does not reach adult levels until
several years of age
 The biotransformation of several drugs and endogenous compounds proceed
through glucuronidation, which is poorly developed in fetal and neonatal life
o Morphin
o NSAIDs
o Acetaminophen
o Bilirubin
o Chloramphenicol (when given to neonates, accumulation of
unmetabolized drug causes hypotension and cyanosis, among other
adverse effects- gray baby syndrome)
Summary:
o Drugs metabolized in the liver show:
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A DECREASE in fetal and neonatal metabolism
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An age-dependent INCREASE in plasma clearance in children younger than 10 as compared to
adults (more efficient clearance in childhood)
ELIMINATION:
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Renal Excretion: contributes to the elimination of water soluble drugs and metabolites
Neonates:
o Immaturity of the kidney limits glomerular and tubular functional capacity, resulting in DECREASED
drug elimination and prolonged half-lives

Neonatal GFR may be as low as 5-10% of adult values

Important to understand to concept to avoid toxicity
o Need to INCREASE dosing interval of drugs excreted by this method (preterm > term > 1 month old)
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Examples: aminoglycoside antibiotics (ie. tobramycin) and milrinone (PDE inhibitor used to
treat pediatric congenital heart disease)
o Nephronal Development:

Begins around 8 weeks gestation and progresses until 36 weeks (in terms of numbers)

Glomerular function blossoms around 34-36 weeks, but low RBF means that GFR remains low
in early infancy
Toddlers:
o GFR gradually increases over the first 2 years of life
o Toddlers have GFRs that are either equal to, or exceed, that of adults

Achieve adults levels of kidney function and renal clearance at this time
AGENTS CAUSING AGE-RELATED ADVERSE EVENTS:
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Basics: medications given to children have to be dose and interval adjusted; there are a few medications that can still
cause adverse events even in the presence of appropriate dosing
Tetracyclines: contraindicated in kids under 8 due to teeth discoloration
Fluoroquinolones: can cause tendon problems in young animal models and has been implicated in poor cartilage
development (use is limited in pediatrics- only used if no reasonable alternative exists)
-
Ceftriaxone: can displace bilirubin from albumin in premature infants and neonates with hyperbilirubinemia,
potentially causing kernicterus (rarely used in neonates due to other alternatives)
PHARMACODYNAMICS:

General:
Very few studies in pediatrics that examine what the drug does to the body
Effects of pediatric pharmacodynamics have not been studied to the same degree as changes in PK

Specific Examples of Differences in Children:
Medications with DA Agonist Effects:
o Children have a greater propensity for dystonic reactions (pediatric brain has a higher proportion of
DA-2 receptors)

Metoclopromide: given as propulsive agent for children with GERD, but also has DA agonism
o DA infusions also used to critical care for catecholamine response in shock (effects on heart and
vasculature may help reverse shock state)
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Neonates have relatively immature catecholamine receptor density and function

Respond poorly to doses that increase HR and BP in older children and adults
Agents producing mild CNS depression:
o Examples: antihistamines, low dose benzos, barbiturates
o Effect in Children: may show paradoxical hyperexcitability following administration (these drugs
normally result in sedation in adults)
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Barriers to Pediatric Studies:
Moral, ethical and technical concerns
Measurement of metabolic enzyme activity requires serial blood/urine collections (because of lower blood
volume, hard to do in kids without causing harm)
Population PK and PD studies are likely going to become more prevalent
o Some flexibility with regard to patient sampling and still yields valid information
o Used to limit number of samples from any one patient (take samples from a variety of patients)