Pediatric Medication Dosing

Introduction and Learning Objectives

• Dosing medications for pediatric patients can be challenging due to limited drug labeling information for pediatric use
• A large percentage of drugs lack data on pediatric dosing, safety, and efficacy
• The younger the age group, the more limited the available information
• A significant portion of medication prescribing for children is considered off-label
• Off-label use includes using a medication for unlisted illnesses, outside licensed age ranges, or with different dosing/administration
• Pediatric patients should not be treated as "small adults" with scaled-down doses due to multiple varying factors
• The preferred drug therapy may vary for certain diseases in pediatric patients compared to adults
• The learning objectives include describing pediatric growth and development influences on drug selection and dosing
• A goal is to explain pharmacokinetic differences in pediatric patients for drug absorption, distribution, metabolism, and elimination compared to adults
• Learning to recognize parameters for estimating creatinine clearance or GFR in pediatric patients is also a goal
• Objectives include incorporating developmental pharmacology principles into medication choices and doses
• Learning to identify key information for appropriate drug dosing in case scenarios is another aim
• A goal is to apply pediatric prescription writing and medication ordering concepts ensuring safe and effective medication administration
• Identifying important considerations for oral and topical formulations in the pediatric population is included
• You should be able to prescribe common drugs for pediatric patient case scenarios

Population and Classifications

• Pediatric patients represents ~25% of the U.S. population (counting those <20 years old), with 6% younger than 5 years
• A survey found 53% of children visiting pediatricians' offices leave with a prescription
• The pediatric population is diverse, with ages that range from premature neonates to adolescents
• Pediatric patient weights vary significantly, ranging from 0.5 kg to 50 kg.
• Pediatric patients are defined as those younger than 18 years, while some clinicians care for patients up to 21
• Pediatric patients' ages can be in days, weeks, months, and years, unlike adult patients
• Pediatric patients are grouped by age to discuss growth and development

Commonly Used Age Definitions

• Premature neonates are born at less than 36 weeks gestational age
• Term neonates are born at 36 or more weeks gestational age
• Neonates are from birth to 1 month of age
• Infants are from 1 month to 1 year of age
• Children are from 1 to 11 years of age
• Adolescents are from 12 to 16 years of age, but the age could exceed 16

Growth and Development

• Children have considerable physiologic changes between birth and adulthood
• The timing of maturation varies from child to child, while most follow the same general pattern of growth
• Changes from birth to adulthood impact drug selection, dose, and administration

Case Application

• For a 4-month-old, 6.5 kg baby boy who has recently started teething, acetaminophen is the most appropriate analgesic
• Aspirin is avoided in children due to the risk of Reye syndrome
• NSAIDs are not recommended for infants < 6 months old due to increased renal impairment risk
• Dosing for this infant should be 10 to 15 mg/kg every 4-6 hours as needed, with no more than 5 doses or 75 mg/kg in 24 hours
• Based on the infant's age and weight, parents should give 65 mg (2 mL) of acetaminophen 160mg/5mL oral suspension every 6 hours as needed

Monitoring and Pharmacotherapy

• Children are regularly monitored for physical, motor, cognitive, and psychosocial development using growth charts
• Head circumference, weight, length/stature, weight-for-length, and BMI are plotted
• Vital signs are assessed in appropriate pediatric reference ranges
• Clinicians must consider the impact of selected drug therapy on physical, motor, cognitive, and psychosocial development.
• Balancing the risk of adverse events versus the potential therapeutic benefit is crucial when treating pediatric patients

Drugs and Impaired Development

• Antiepileptic drugs: can impair cognitive and physical development
• Stimulant drugs for ADHD: can impair growth
• Antipsychotics: can impair motor skills
• Benzodiazepines: can impair cognitive functions
• Corticosteroids (systemic, inhaled): can impair growth
• Isotretinoin: can cause psychological effects

Pediatric Pharmacokinetic Differences

• All aspects of pharmacokinetics are affected by a child's growth and development

Absorption

• Drug absorption differs because of gastric pH, GI motility, intestinal flora and enzymes, integumentary development, and musculoskeletal anatomy, especially in a baby's first months of life
• Gastric fluid volume is reduced at birth
• Neonates have a higher, nearly neutral stomach pH due to decreased gastric acid production which results in greater absorption of acid-labile drugs but reduced absorption of weakly acidic drugs
• Gastric acid output increases during the first 1 to 2 weeks and reaches adult values at 2 to 3 years old
• Bile acid transport and pancreatic enzyme production is reduced, altering pH-sensitive drug absorption and reducing enterohepatic recirculation
• Amylase activity is minimal at birth and remains low until the third month of life
• Gastric lipase is present at birth and accounts for a greater percentage of fat absorption during early life
• Neonates are born with sterile GI tracts, and have normal bacterial colonization that occurs within days for term infants, but may be delayed in premature infants in the ICU impacting the effectiveness of drugs that rely on gastrointestinal flora for activation or degradation
• Gastric emptying is delayed, and intestinal transit time is prolonged at birth, but increases within the first few days
• Premature infants have delayed gastric emptying and intestinal transit
• In a study of acetaminophen dosing, premature infants at 28 weeks' gestational age had a 2-hour delay in absorption compared with older infants
• Adult values for gastric emptying and intestinal transit time are reached by 4 to 8 months

Passive Diffusion

• For drugs absorbed through passive diffusion, reduced splanchnic blood flow during the first weeks reduces the rate and extent of absorption
• Reduced blood flow may place neonates at risk for gut lining damage from hyperosmolar drug formulations, so some institutions delay enteral drug administration until the patient receives 1/4 to 1/2 of their nutritional needs through enteral feedings
• Reduced first-pass metabolism of drugs are given enterally due to lower levels of metabolic enzyme activity in the intestine
• The bioavailability of zidovudine decreased from 89% in neonates during the first 2 weeks of life to 61% in older infants, reflecting increased first-pass metabolism, and intestinal enzymatic activity does not approach adult values until 2 to 3 years old

Case Application

• A 1.5-kg, 4-week-old infant girl born at 29 weeks' gestational age treated with IV phenobarbital for seizures is being transitioned to oral therapy
• The prior trough serum phenobarbital concentration was 17.5 mcg/mL
• After switching to PO phenobarbital elixir, concentration was only 8.9 mcg/mL after 1 week
• A lower phenobarbital serum concentration after enteral therapy is the result of reduced drug absorption in GI tract, because of the higher gastric pH and the reduced splanchnic blood flow
• To achieve desired trough concentration, the medication dose will need to be increased

Intramuscular Drug Absorption

• Typical neonates have decreased muscle blood flow and are fairly immobile
• Neonates have an increased percent water content per muscle mass
• A significant decrease and erratic rate of absorption for IM medications in the neonatal population
• A similar delay in drug absorption may occur with subcutaneous injection due to lower percentage of body fat
• Delayed absorption is a disadvantage when rapid absorption is needed, such as antibiotics
• The delay in absorption seen with IM and subcutaneous administration becomes negligible after the first months of life
• Delayed systemic absorption after IM injection in the neonate is an advantage for phytonadione (vitamin K) administration after birth by providing a slow release of the drug into the systemic circulation

Transdermal Drug Absorption

• Transdermal and percutaneous administration results in greater drug absorption in neonates
• Percutaneous absorption is directly related to skin hydration and inversely related to stratum corneum development
• Preterm neonates have an extremely undeveloped (thinner) stratum corneum putting them at increased risk for toxicity with topical agents like hexachlorophene, povidone-iodine, corticosteroids, alcohol, and polymixin
• Pediatric patients continue to absorb medications more rapidly than adults because of cutaneous perfusion and body surface area relative to weight
• Common topical products can produce systemic toxicity which includes using hydrocortisone-containing diaper rash products which can lead to suppression of the hypothalamus-pituitary-adrenal axis when used for 2 weeks or more
• To safely use povidone-iodine for a procedure, use only 10% solution on the affected area before surgery and remove after within 5 to 10 minutes

Topical Administration

• Low concentrations of topical anesthetics such as 4% lidocaine and EMLA are safe before venipuncture or circumcision
• After one year or older, transdermal application becomes more useful
• Methylphenidate and clonidine patches are used for ADHD treatment in school-aged children
• Lidocaine and fentanyl patches are used for severe pain treatment in older children and adolescents

Rectal Drug Absorption

• Rectal administration may be useful when severe nausea and vomiting or status epilepticus occur
• Most drugs can be absorbed rectally but infants may have an inability to retain suppositories long enough for optimal absorption due to rectal contractions
• Gels and liquid formulations that don't require dissolution avoid suppository retention issues
• Drugs supplied via rectal formulations include acetaminophen suppositories or rectal diazepam gel
• For medications that undergo extensive first-pass metabolism, bioavailability may increase through rectal administration compared to oral administration
• Some drugs have reduced bioavailability administered rectally
• Drug dosing references recommend a slightly higher rectal acetaminophen dose of 10-20 mg/kg due to lower bioavailability

Intranasal Drug Administration

• Intranasal midazolam has been compared to rectal diazepam for acute seizure treatment in pediatric patients

Distribution

• Distribution is affected by changes in relative organ size, body water content, fat stores, plasma protein concentrations, acid-base balance, cardiac output, and tissue perfusion, particularly during the first year of life

• Water makes up about 80% to 85% of a typical premature infant's body weight, approaching adult values of 55-60% at one-year-old

• The ratio of intracellular to extracellular fluid is nearly equal in infants at that age compared to adults

• The ratio of intracellular fluid increases relative to that of extracellular fluid throughout infancy/childhood to adulthood

• The apparent volume of distribution (Vd) is normalized, based on body weight and measured in L/kg

• Extracellular fluid and total body water per kg of body weight are elevated in neonates and infants, therefore, water-soluble drugs have higher Vd and doses of water-soluble drugs may need to be increased

• Aminoglycosides given at higher individualized doses are common

• The volume of distribution of gentamicin in premature neonates ranges from 0.5 to 0.7 L/kg, reflecting higher extracellular water content at this age, but falls to 0.4 L/kg by the end of the first year and declines to 0.2 -0.3 by adulthood

• Because of their higher volume of distribution, the weight-based dose for an infant is often higher than comparable dose in an adult

Body Fat and Protein Binding

• As with body water composition, adipose composition changes dramatically in pediatric patients
• Variability in newborns likely, with 1% body weight for premature babies and closer to 15% for full-term
• The neonate fat composition may be 57% water and 35% fat, adults appoach 26% and 72%
• Increasing rates of childhood obesity has generated concerns about efficacy and safety of weight-based dosing strategies
• Serum concentrations of protein, binding affinities of proteins, and competition for binding sites are the essential characteristics for protein binding and dosing

Protein

• Albumin and α-1 acid glycoprotein are the proteins most responsible for binding acidic and basic drugs
• Levels of both are low in neonates and gradually increase at one-year-old
• In neonates the normal albumin serum concentration is 2 to 4 g/dL
• In neonates fetal albumin may persist and albumin, like previously stated, also has a lower affinity for many drugs
• With competition, neonatal and infant albumin binding can decrease with drugs/endogenous substances as compared to adults
• Phenytoin is 90% protein bound in adult
• With phenytoin 10% is available for activity
• An adult with 20 mg/L of phenytoin should have 2 mg/L unbound in serum
• Neonates with similar serum levels would be associated with a much larger unbound fraction with a phenytoin concentration of 20 mg/L in adults is at the upper limit of treatment

Kernicterus Risk

• Highly protein-bound drugs (phenytoin, aspirin, sulfonylureas, sulfamethoxazole, or ceftriaxone) can displace bilirubin in neonates
• Increased blood-brain barrier permeability in neonates can lead to kernicterus
• Sulfonamides are not recommended or approved for use in 0–2 month-old infants
• Ceftriaxone can be approved but is contraindicated with hyperbilirubinemia
• Drugs with greater unbound concentrations in neonates than in adults are: Alfentanil, Ampicillin, Ceftriaxone, Cefuroxime, Diazepam, Digoxin, Ketamine, Lidocaine, Morphine, Nafcillin, Penicillin G, Phenobarbital, Phenytoin, Propranolol, Salicylates, Sulfonamides, Theophylline, and Valproic acid

Tissue Perfusion and Metabolism

• Greater distribution into the central nervous system can occur in the neonatal period because an infant's brain makes up 10-12% of body vs adult's 2%, the percentage systemic blood flow reaching cerebral vasculature is greater and, third, passage is easier due to the blood-brain barrier
• Toxicity can result, like in the meningitis or seizures
• Aminoglycosides aren't thought to have adequate penetration in adults, but possess adequate distribution in neonates
• Some central acting agents like morphine sulfate, chloral hydrate, and phenobarbital pose toxicity
• Displacement of bilirubin leads to kernicterus

Metabolic Function

• Half-life differences have been identified during infancy, childhood, and adolescence
• Some enzymes exhibit metabolic activity in utero as others develop months later
• Enzyme development continues and is not complete until after puberty
• Enzyme development can be affected by health, nutritional status and exposure to substrate and genetic polymorphisms
• Drug metabolism increases water solubility and enhances drug clearance which either makes several therapeutic or toxic metabolites
• Phase I and II reactions occur through the hepatic microsomal enzyme system (cytochrome P450) to include oxidation, reduction, hydrolysis, glucuronidation, sulfation, and acetylation
• Development of these are key factors that affect pediatric dose and should be reviewed

Metabolic Enzyme Systems and Development

• Alcohol dehydrogenase common substrate is benzyl alcohol and present in utero in amounts of under 5% adult which approaches maturity around 5 years and leads to FDA recommneding use of preservative free preparations in newborns
• CYP2E1 has acetaminophen as its common substrate and is lacking in adults but increases until a third month which impacts metabolite formation
• CYP2D6 has a common substrate of atomoxetine with increased rapid activity demonstrated during the third trimester which is similar to adults and has an example of impact of genetic polymorphisms related to changes in heart rate
• CYP2C9 features warfarin/valproic acid/phenytoin and has low activity which grows to 25%
• CYP2C19 and CYP1A2 have similar amounts of development and activity but can increase over time which are seen to be impacted by common substrates
• CYP3A4 levels rise to meet the decline of CYP3A7 with adults at 6-12 months whose enzymes may exceed adult activity and related substrate is erythromycin and UGT, SULT which have morphine and acetaminophen related substrates and lower increases of activity
• UGT expressions vary and can lead to accumulation of increased compound resulting in gray baby
• Sulfation is the primary first year of metabolic which leads to a primary route and glucaronide to begin predominately

Elimination

• Elimination is reduced during infancy which use to estimate of Use of Creatinine requires many equations
• GFR is not developed in neonates and is very low and the levels increases through childhood
• In babies who are born prior to 34 weeks it will have levels that take them longer to get correct

Examples of Vancomycin and Aminoglycoside

• Vancomycin is often given between every 18 to 24 hours to LBW every 6 hours in those with normal renal function and 8 to 12 in normal function patients
• Antibiotics are considered to be 90% likely via glomerular filtration but there are risks associated with weight of nephro and ototoxicity
• Typical weight of the neonate is appropriate at first but therapeutic because in the second the GFR will climb
• Cystic fibrosis children are compared to those with antibiotics and higher doeses are to weigh with interval
• Tubular and its bases are used at capacity and for at birth to get enough capacity it increases
• Reduction of tubular has a half-life of Penicillins digoxin and more of a 1 and older
• In premature doses get dosed 12 hours and for the older kids it needs 6 hours
• The serum creatinine values come off the placenta into maternal and elevated
• A low function is in place for muscle mass and babies that are early will want to weigh

Important Formulas to Note

• There are equations for adults for the kidneys and the use of IDMS with CrCl for the GFR: GFR mL / min /1.72
• Adolescence isn't simply a point with the effects puberty has

Puberty Points of Note

• Puberty has different phases and effects
• Hormonal and puberty maturation happen
• Kidneys can filter but may not
• The dose of morphine is used
• Must encompass changes for pain
• Pain is a great indicator of rates

Pharmacodynamic differences

• Impact changes during therapy and responses to them
• Changes and transduction happen through maturity
• Infants lack or are relative for some of agonists
• May see reduction in receptiveness
• Some fold might help lower blood pressure
• It's important to supplement

Adverse effects

• the Label includes black box for serious skin
• the ration if 0.9 to 8 year olds but a 3 percent for adults
• In glucuronidation they were similar to ones that had lower rate than them
• Some are suspicious to immune mediated responses

Dosing in Pediatrics

• Pharm and dynamics children influenced dose
• Difficult use makes weight estimate. mg/kg, mcg /kg/DOSE
• Exception in chemotherapy
• May be accurate for younger that may account for diff volume
• Gentamicin based on post weight. And dose is appropriate

Pediatric Formulation

• Need for medication differs on patients
• With topicals that can be steroids those can be bad
• The lower potency is needed
• Avoid increasing
• Can be too greasy for certain area
• Some is ok, lotion is for not dry, and others that may sting
• Specific things can be followed until the redness has settled
• Given how and where to dose or indicate
• Check to see where the skin had issues or where best to use

Side Effects of Steroid Treatment

• Potential side effects-
• Skin conditions
• Dermatitis
• Atrophy or not in color
• Other things
• Stero
• And others like anti

Anti Contamination

• Use anti to not make skin not bad for you
• Only minimize other exposure
• Emollient- least contact with dermatitis

Pure Vaseline

• More safe for them not to get diarrhea
• Use lotion that gets you the skin problems
• Give IV in people and where to make small doses diluted
• For high people restrict
• Take a dosage and oral
• Take all you need in a liquid to make palatitive
• Be aware though of infections
• Use oral with pharmacies to make it easier to take

Medication Orders

• Prevent errors
• Look for the causes that lead
• Double check
• Check ALL
• Correct in weight
• Use units
• All things should be checked
• If the order is to be filled check with where to refill
• Technology may minimize or give information
• For pre make sure the units and amount is what is needed
• Ten folding
• Should not not be with
• It needs a way to dose and give all

Medication instructions

• Read the list and ensure the caregiver receives it to dose
• Check concentrations and round for the correct patient
• Use with narrow
• Make sure things can be checked for correct amount
• NOT use spoons

Steps for Calculating

• Convert
• Add numbers
• Check weights
• Take to the other area

Common Pediatric Drugs

• Similar doses are like ibuprofen and others
• More that are similar and what you can see
• Table is on doses too
• With those over the limit that may lead to cough and more

Amox and Ibu

• Ibu is similar for ages 6+, more might be with mild fever
• And what type needed for that
• Amox is for kids
• For infants 3 moths receive for them over those
• Child's weight is for the ones
• Doses are for what they are used for And other table info on it all

Antibiotics and Contradictions

• Dosage is with Amox
• That can lead to issues
• Suspects for a drug
• Check weight range with the charts
• Dose: Number
• The chart will show how much

Ceftriaxone info

• Check IV
• Look for those types
• Check what can add up to these

Albuterol side effect

• Albuterol is for treatment
• Kids can have that if use it then and it can be with help if not great with
• Then the dosage can be done through body weight
• Should not exceed all four vials with the

Other tips

• That should be for help
• Order can be given with those types.
• Then with things from the chart.