Prescribing for Pediatric Patients

Gastric fluid volume is

greatly reduced at birth. Gastric acid production is decreased, giving the neonate a higher, nearly neutral pH in the stomach. This results in a greater absorption of acid-labile drugs such as penicillin G and erythromycin, but reduced absorption of weakly acidic drugs such as phenobarbital and phenytoin.

Corticosteroid; systemic, inhaled

growth

Stimulant drugs used for attention deficit hyperactivity disorder

growth

Students should have a general idea of relative potencies of corticosteroid creams. There is some overlap, influenced by concentration and formulation such as cream < ointment. Example order of potency from least to greatest:

hydrocortisone, triamcinolone < mometasone, betamethasone < halcinonide, clobetasol, halobetasol

Adolescent

12 - 16 years of age (some may go higher)

Antiepileptic drugs

cognitive, growth

Isotretinoin

psychological

Child

> 1 - 11 years of age

Premature neonate

Born at < 36 weeks gestational age

Term Neonate

Born at > 36 weeks gestational age

Antipsychotics

motor

SOME PROTOTYPICAL OR COMMONLY USED PEDIATRIC DRUGS AND DRUG DOSES.

• Acetaminophen - Similar doses are administered for treatment of pain or fever in children. Be aware that liquid formulations are available in varied concentrations. "Drops" (100 mg/mL) are more concentrated than other available liquids or suspensions 160 mg/5 mL. Tablets are available in chewable (80 or 160 mg/ tab), orally disintegrating, and conventional tablets (325 mg/tablet). The recommended pediatric dose for acetaminophen is 10 to 15 mg/kg per dose with a maximum of 5 doses per 24 hour period. Acetaminophen may be dosed by age or weight - table includes sample dose amounts

Glomerular filtration rate (GFR) is appreciably

underdeveloped in the neonatal population. Most neonates exhibit a GFR 20 to 40 mL/min/1.73m2. Soon after birth, increased renal blood flow becomes apparent within the first week and GFR begins to increase with age. By 6 months GFR increases to 80 to 110 mL/min/1.73 m2 and continues to approach adult values by 1 year of age. The picture is much different, however, for premature neonates. In babies born before 34 weeks gestation, substantial nephrogenesis has yet to occur. Therefore, preterm neonates have even lower GFRs at birth and do not "catch up" with full term neonates until 5-6 weeks of age. The relatively low GFR at birth and the subsequent dramatic increases in GFR that occur in the first few weeks of life lead to drug dosing challenges in pediatric patients, particularly with medications that are eliminated primarily through filtration. Examples:

GFR (mL/min/1.73 m²) =

(0.41 × Height in cm) / serum Creatinine in mg/dL

Drugs that are highly protein bound

(phenytoin, aspirin, sulfonylureas, sulfamethoxazole, ceftriaxone) have been shown to displace bilirubin in neonates. Because of the increased blood-brain barrier permeability seen in neonates, this displacement of bilirubin has occasionally led to kernicterus, neurologic damage caused by deposition of bilirubin in the brain, primarily the basal ganglia. For this reason, sulfonamides are not recommended for neonates and are nto approved by the FDA for use in infants younger than 2 months of age. Ceftriaxone, which is also highly protein bound, is approved for use in neonates, however, it is contraindicated in those with hyperbilirubinemia. As a precaution, many hospitals restrict its use in the neonatal population to only those patients who have infections resistant to other antibiotics

CYP2D6

*Atomoxetine*, amitriptyline, codeine, lidocaine, methadone, metoprolol, fluoxetine, vincristine Recent research has demonstrated that CYP2D6 activity increases rapidly during the third trimester, and by the second week of life, values are similar to values in adults, and remain constant throughout childhood. Genetic polymorphisms have similar impact compared to adults. Example: poor metabolizers taking atomoxetine have greater increased in heart rate and blood pressure compared with extensive metabolizers taking comparable doses.

UGT (uridine 5'-diphsophate glucuronosyltransferase) glucuronidation

*Morphine*, valproic acid, *chloramphenicol*, acetaminophen Present in low levels in fetal hepatic and renal tissues. Gradual increase in first 6 months of life, sill lower than adults for first 2 to 3 years of age. Genetic polymorphisms lead to variation in UGT expression. Example 1: Reduced activity of UGT2B7, primary enzyme for chloramphenicol metabolism, allowed accumulation of parent compound resulting in "gray baby syndrome". Example 2: glucuronidation of morphine occurs in premature neonates but at a much slower rate compared to term neonates. Morphine metabolism increases rapidly between 24 and 40 weeks post-conceptional age, however still substantially slower compared to adults until about 3 years of age. For premature infants, morphine should be initiated at lower doses than those recommended for infants and children.

CYP2C9

*Phenytoin*, warfarin, Valproic acid About 1% activity in fetal hepatocytes, with very low activity in newborn reaching about 25% adult values by 5 months of age. Remains at only 50% of adults until after puberty. Genetic polymorphisms have similar impact compared to adults. Example: the apparent (MM) half-life of phenytoin in premature infants is about 75 hours compared with 20 hours in term neonate and 8 hours in a 2 week old.

CYP2E1

Acetaminophen Lacking in first trimester, appear in second trimester. Approximately 10% to 20% of adult levels at birth Increase until 3 months of age when CYP2E1 expression is similar to adults. Impacts acetaminophen metabolite formation.

In addition to these differences, neonates are also born with relatively sterile gastrointestinal tracts.

. Normal bacterial colonization typically occurs within days for term infants, but may be delayed in premature infants who reside in the more sterile environment of an intensive care unit. The effectiveness of drugs that rely on gastrointestinal flora for activation or degradation may be significantly altered during this period.

Pediatric patients are defined as those younger than

18 years, although some pediatric clinicians may care for patients up to age 21. The age of adult patients is consistently measured in years, while a pediatric patient's age can be expressed in days, weeks, months, and years. To discuss the changes that occur with growth and development, pediatric patients are typically grouped by age as shown in the table below.

Body Fat:

: As with body water composition, the body adipose composition also changes dramatically in pediatric patients and may affect drug distribution (Figure 1). The variability is probably greatest with newborns.

Infant

> 1 month - 1 year of age

Case application: A 16-year-old, 67-kg boy with osteosarcoma has received morphine for pain throughout his numerous hospitalizations for surgery and chemotherapy during the past 2 years, requiring an infusion rate as high as 0.5 mg/kg/hour. During this period, he has progressed through puberty and is now a mature adult male. When his morphine infusion rate is initiated at a dose similar to his last hospitalization, it is noted that he is having excessive sedation. What might explain the change in A.M.'s response to morphine?

A study of adolescents receiving morphine for sickle cell crisis showed that postpubertal adolescents, have weight-normalized clearance values 30% lower than younger patients during early puberty, suggesting a possible reduction in UGT2B7 activity. The titration of this patient's morphine must encompass not only the changes in drug clearance resulting from growth and development but also the progression of his disease and his need for pain control. Assessment of pain, using frequent self-report or a standardized pain scale, as well as heart rate, blood pressure, and respiratory rate, is essential for appropriate adjustment of the morphine infusion.

Changes during puberty

Adolescence is not simply a link between childhood and adulthood; it is a distinct period of significant physiologic change. The effects of puberty can alter the efficacy or toxicity of many drugs administered during this period. Although most evidence focuses on differences in neonatal pharmacokinetics, it is recognized that puberty may influence drug distribution. Hormonal fluctuations and sexual maturation can alter efficacy or toxicity of drugs during this period. Drug distribution can be altered as a result of an increase in body fat. Increases in serum protein concentrations occur during puberty and may alter drug binding

Examples of drugs with greater unbound concentrations in neonates than in adults are listed below:

Alfentanil Lidocaine Phenytoin Ampicillin Ketamine Propranolol Ceftriaxone Morphine Salicylates Cefuroxime Nafcillin Sulfonamides Diazepam Penicillin G Theophylline Digoxin Phenobarbital Valproic acid

PEDIATRIC PHARMACOKINETIC DIFFERENCES

All aspects of pharmacokinetics are affected by growth and development.

This can lead to risk for toxicity in the neonate/infant or can produce therapeutic benefits, such as in treatment of meningitis or seizures.

Aminoglycosides are not thought to have adequate penetration into the CNS in adults, but have adequate CNS distribution in the neonate (part of preferred empiric antibiotic regimen).

CYP3A4 (and CYP3A7 and CYP3A5

Amiodarone, cyclosporine, carbamazepine, *erythromycin*, lidocaine, warfarin CYP3A7: primary enzyme present in utero. Found in first trimester to serve in transformation of fetal dehydroepiandrosterone and detoxification of retinoic acid derivatives transferred from maternal serum across placenta. Declines reapidly after birth and typically undetectable after 1 year of age. CYP3A4 and 5: levels rise as 3A7 declines. 3A4 is present in utero but about 100 fold less than 3A7. CYP3A4 increases over first months of life, with adult activity reached at 6 to 12 months. Children 1 to 4 y may exceed adult activity with return to adult activity at puberty. 3A5 is highly variable and not thought to be related to age. Example: erythromycin used in a neonate to increase gastrointestinal motility will have a slower rate of metabolism, thus should be dosed conservatively.

Levels of both proteins are

extremely low in neonates and gradually increase to approximate adult values at 1 year of age. The normal albumin serum concentration in neonates and infants is 2 to 4 g/dL

Alcohol dehydrogenase

Benzyl alcohol (preservative in injectable drug solutions) Present in utero in amounts < 5% of adult levels. Enzyme activity approaches functional maturity around 5 years of age. Exposure to the preservative benzyl alcohol and benzoic acid metabolite leads to potentially fatal toxicity. FDA recommends use of preservative free (PF) or preparations with alternative preservatives in newborns. There may be some drugs used in premature or critically ill neonates that are not available in PF preparations. Total daily toxicity threshold for exposure ~ 99 mg/kg/day.

MEDICATION DOSING IN PEDIATRIC PATIENTS

As previously discussed, the differences in pharmacokinetics and pharmacodynamics observed in children influence the choice of dose and dosing interval. Because incorporating all of these variables would result in dosing calculations too difficult for practical use, weight has traditionally been chosen as the single best estimate of growth. Pediatric drug references provide most doses in units per weight, such as mg/kg/day or mcg/kg/dose. An exception to this is chemotherapeutic agents, which are dosed by body surface area, incorporating height as an additional variable. Because of the difficulty in accurately determining height (or length) in young children, it is not commonly used for other drugs. Age can be an important variable, especially for premature infants, in whom it can be used to account for differences in volume of distribution and elimination half-life. For example, neonatal gentamicin dosing is often based on a rubric of gestational or postconceptional age, postnatal age, and weight. Older children and adolescents should transition to adult dosing whenever the calculated weight-based dose exceeds the usual adult dose.

Neonate

Birth - 1 month of age

CYP1A2

Caffeine Non-existent in fetal liver and in newborns who were not exposed to caffeine in utero. Newborns exposed to caffeine in utero have higher levels of CYP1A2 at birth. Enzyme activity rises during first month of life, by 6 months may exceed adult values. Example: Caffeine used for treatment of apnea has a longer half-life (once a day dosing) in neonates. By 6 months, an infant may need increased dosing due to increased enzyme activity (shorter half life). but achieves adult activity at 4 months. Children 1 to 2 years of age may exceed adult activity with return to adult activity at puberty.

PEDIATRIC PHARMACODYNAMIC DIFFERENCES

Changes in pharmacodynamics during growth may also impact drug therapy responses in children. These are not as well studied as pharmacokinetic changes. A few examples include:

GROWTH AND DEVELOPMENT

Children undergo considerable physiologic changes between birth and adulthood. Although most follow the same general pattern of growth, the timing of maturation varies from child to child. These changes between birth to adult hood will impact selection of drug, dose, and route of administration.

SULT (sulfotransferase) sulfation

Chloramphenicol, acetaminophen Sulfotransferases develop extensively in utero, reaching levels of activity similar to adults at birth. Intrauterine expression of various SULT enzymes are responsible for fetal metabolism of thyroid hormones, steroid hormones, and catecholamines. Sulfation is an important pathway in metabolism of morphine during early infancy as well as catecholamines, thyroid hormone, theophylline, and acetaminophen. Example: in the first year of life sulfation of acetaminophen is a primary route of metabolism, the glucuronide pathways begin to predominate later in infancy.

Tissue Perfusion:

Drug distribution into the central nervous system is higher in the neonatal period for several reasons: 1. The brain makes up 10% to 12% of the weight of an infant, while it constitutes only 2% of total body weight in an adult; thus a larger potential compartment for drug distribution. 2. The percentage of systemic blood flow that reaches the cerebral vasculature is greater. 3. Greater passive diffusion of drugs across the functionally immature blood-brain barrier.

Distribution

Drug 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. The greatest degree of change occurs during the first year of life.

Elimination

Elimination is reduced during infancy, resulting in slower rates of clearance for many commonly used drugs. Glomerular filtration rate increases throughout childhood. Use of creatinine clearance as an estimate of glomerular filtration rate requires different equations than those used in adults.

Case application: A 4-month-old, 6.5 kg baby boy who has recently started teething. His parents ask for advice on a medication to alleviate C.J.'s pain.

For this case, acetaminophen is the most appropriate analgesic. Aspirin is not used in children because of its association with Reye syndrome (rare condition causing mitochondrial damage and resulting in hepatic failure). NSAIDs are not recommended for use in infants younger than 6 months of age due to an increased risk for renal impairment. This infant should receive a dose of 10 to 15 mg/kg every 4 to 6 hours as needed with no more than 5 doses or 75 mg/kg given in a 24 hour period. Based on his age and weight, his parents would give 65 mg (2 mL) of the acetaminophen 160mg/5mL oral suspension every 6 hours as needed. See important acetaminophen dosing information on page 18.

Antiseptics are another class of topically administered medications.

Hexachlorophene is now avoided in neonates secondary to the development of neurotoxicity (not extensively used for any patient population today). Chlorhexidine is commonly used for pediatric patients. The use of topical iodine as an antiseptic in the pediatric population has been associated with dermatologic side effects ranging from allergic contact dermatitis to cutaneous necrosis. There may also be some risk of hypothryroidism to young infants exposed to topical iodine. Whatever topical antiseptic is chosen for pediatric patients, exposure to isopropyl alcohol should be minimized. Several products that contain isopropyl alcohol 4% or less are available and are generally considered safe in pediatrics.

gastric lipase is

In contrast, gastric lipase is present at birth and accounts for a greater percentage of fat absorption during early life

Intranasal Drug Absorption:

Intranasal administration is being explored as an alternative route for some pediatric therapies. For example, intranasal midazolam has been compared to rectal diazepam for acute seizures in pediatric patients with epilepsy.

Metabolism

Metabolic function is highly dependent on patient age. This has been demonstrated in a number of recent studies, which have identified significant differences in half-life during infancy, childhood, and adolescence.

After age 1 year or older, transdermal application becomes more useful.

Methylphenidate and clonidine patches are used in the treatment of attention deficit hyperactivity disorder in school-aged children. Lidocaine and fentanyl patches are used for treatment of severe pain in older children and adolescents.

• When oral drug therapy is needed, one must also consider the type of dosage form available. Children younger than 6 years are often not able to swallow oral tablets or capsules and may require oral liquid formulations. Before writing a prescription, the child's ability to swallow a solid dosage form should be assessed.

Not all oral medications, especially those unapproved for use in infants and children, have a commercially available liquid dosage form. Use of a liquid formulation compounded from a solid oral dosage form is an option when supportive data are available (e.g., clonazepam, rifampin). Pharmacies can sometimes add flavors to certain liquid medications to improve palatability. If no interactions exist, doses can be mixed with food items such as pudding, fruit-flavored gelatin, chocolate syrup, applesauce, or other fruit puree immediately before administration of individual doses. Since honey may contain spores of Clostridium botulinum, it should not be administered to infants younger than 1 year due to increased risk for developing botulism. The inpatient pharmacies at the hospitals where care is provided to pediatric patients are usually able to compound formulations in their inpatient pharmacy. Limited accessibility to compounded oral liquids in community pharmacies may pose a challenge. Prescribers should work with pharmacists to find community pharmacies with compounding capabilities and maintain and provide a list to parents and caregivers before discharge from the hospital.

CYP2C19

Phenytoin, omeprazole, *pantoprazole*, diazepam Small amount of development in utero, with 10% to 20% enzyme activity at birth compared to adults. Increases to near adult values by third month of life. Genetic polymorphisms have similar impact compared to adults. Example: pantoprazole half-life longer in term neonates and premature infants compared to adults. Also increased drug concentration in patients who were poor metabolizers.

Drugs/drug classes associated with impaired development*

Potentially impaired developmental effect or adverse effect

PEDIATRIC MEDICATION ORDERS AND PRESCRIPTION WRITING

Prevention of errors in pediatric drug therapy begins with identification of possible sources. Medication errors among hospitalized pediatric patients are an all too common occurrence which can lead to potential morbidity and mortality. The reported error rate for hospitalized pediatric patients has been reported to be as high as 1 in 6 orders. This higher frequency compared to adult inpatient error rates has been attributed to off-label use of medications and incorrect dosage calculations. The most common errors among pediatric inpatient admissions are related to incorrect dosage calculations. Another part of safely administering medications to pediatric patients is ensuring that the medication orders and/or prescription are clear to reduce dispensing errors. The error rate among outpatient pediatric prescribing has not been reported, but similar problems are suspected. An additional problem is that many drugs and doses that are used in pediatrics may not be as familiar to community pharmacists compared to pharmacists working in a pediatric institution. And finally, the dosing directions must be clear and simple for the parent or caregiver to follow.

Rectal Drug Absorption:

Rectal administration may be used as a route of drug delivery in pediatric patients. It may be useful in cases of severe nausea and vomiting or status epilepticus. Most drugs are well absorbed by this route, however, among infants; the strong rectal contractions can result in an inability to retain suppositories for the length of time needed for optimal absorption. Gels and liquid drug formulations that do not require time for dissolution are the best options. A limited number of drugs are supplied in rectal dosage forms (e.g., acetaminophen suppository, rectal diazepam gel). Rectal use of oral or parenteral dosage forms are sometimes used in situations with limited options. This use may be based on limited studies, case reports, or simply provider experience.

Example 2: inpatient antibiotic order Calculate the dose of ceftriaxone in mLs for meningitis for a 5 year old weighing 18 kg. The dose required is 100 mg/kg/day divided BID.

Step 1: calculate the dose in mg 18 kg x 100 mg/kg/day = 1800 mg/day Step 2: divide the dose by the frequency 1800 mg/day ׃ 2 (BID) = 900 mg/dose given every 12 hours The pharmacy will convert the dose to volume to be administered and will label the dose with concentration, dose, and volume.

Steps for calculating doses and writing prescription: Example 1: outpatient prescription Calculate the dose of amoxicillin suspension for otitis media for a 1 year old weighing 22 lbs. The dose required is 80 mg/kg/day divided BID and the suspension comes in a concentration of 400 mg/5mL.

Step 1: convert lb to kg 22lb x 1 kg/2.2lb = 10 kg Step 2: calculate the dose in mg 10 kg x 80 mg/kg/day = 800 mg/day Step 3: divide the dose by the frequency Order to pharmacy includes patient weight, dose, frequency 800 mg/day ׃ 2 (BID) = 400 mg/dose given 2 times daily (q 12 hours) Step 4: covert the mg dose to mL Pharmacy and prescribers should tell parent/patient how much to take and how often 400 mg/dose ׃ 400 mg/5mL = 5 mL q 12 h Step 5: figure duration and quantity Minimum volume to supply, anticipate wasted doses 2 doses/day x 5 mL/dose x 10 days = 100 mL

PEDIATRIC ADMINISTRATION AND FORMULATIONS

The administration of medications to pediatric patients often requires innovation. The route of administration will depend on age, disease and severity of disease.

Protein Binding:

The characteristics of protein binding most essential to this discussion are: serum concentrations of protein, binding affinities of proteins, and competition for binding sites.

Drug absorption is altered by a variety of mechanisms, with the most significant differences noted during the first months of life.

The factors most responsible for differences in absorption between pediatric and adults patients are: gastric pH, gastric and intestinal motility, intestinal flora, metabolic enzymes within the gastrointestinal tract, integumentary development, and the musculoskeletal anatomy.

Case application: A 1.5-kg, 4-week-old infant girl born at 29 weeks' gestational age, is being treated with phenobarbital for seizures associated with a period of asphyxia at birth. She is currently receiving a maintenance dose of 7.5 mg (5 mg/kg) given intravenously (IV) once daily. The team wishes to transition her to oral therapy now that she is receiving full enteral feeds. A trough serum phenobarbital concentration obtained during IV therapy was 17.5 mcg/mL, within the desired range of 15 to 40 mcg/mL. Switching the patient to phenobarbital elixir 7.5 mg given orally once daily results in a serum concentration of only 8.9 mcg/mL after 1 week of therapy. What factors might explain the lower concentration, and how should A.H. be managed?

The lower phenobarbital serum concentration after the infant was placed on enteral therapy is most likely the result of reduced drug absorption in the gastrointestinal tract, resulting from the higher gastric pH and reduced splanchnic blood flow. An increase in the maintenance phenobarbital dose will be needed to achieve a trough serum concentration within the desired range.

Premature babies may have only 1% of the body weight as fat, while a full-term neonate has closer to 15% of his/her body weight composed of fat. Also, the fat composition differs between neonates and adults.

The neonate may be 57% water and 35% fat, while values in an adult would approach 26% and 72%, respectively. The increasing rate of childhood obesity has generated concern about efficacy and safety of weight-based dosing strategies. However, the need to make dosage adjustments in obese children remains controversial. There is little evidence to direct dosing.

POPULATION AND CLASSIFICATION OF PEDIATRIC PATIENTS

The pediatric population makes up about 25% of the US population (when counting < 20 years of age) and 6% are younger than 5 years of age. Although most children are healthy, a survey conducted in pediatricians' offices found that 53% of children left their visi with a prescription. The pediatric population is diverse, patients range in age from premature neonates to adolescents and vary in weight by 100 fold from a 0.5 kg premature neonate to a 50 kg 16 year old.

Intramuscular drug absorption:

The typical neonate has relatively decreased blood flow to muscles, is fairly immobile, and has an increased percent water content per muscle mass. This combination of factors leads to a significant decrease and erratic rate of absorption for medications administered intramuscularly in the neonatal population. A similar delay in drug absorption may occur with subcutaneous injection because of the lower percentage of body fat in neonates. This would be a disadvantage when rapid absorption is needed, such as with antibiotic administration. The delay in absorption seen with IM and subcutaneous administration becomes negligible after the first months of life.

Although these physiological characteristics of the pediatric integumentary system may lead to increased toxicity with many agents, they also provide an alternative route of administration.

Topical anesthetics such as 4% lidocaine and EMLA (eutectic mixture of local anesthestics; lidocaine and Prilocaine) are widely used for infants and children before venipuncture, IV catheter placement or circumcision. With the low concentrations and limited duration of contact (30 to 60 minutes) these have been shown to be safe.

Transdermal drug absorption:

Transdermal and percutaneous administration results in greater drug absorption in neonates than it does in older children and adults. Percutaneous absorption is directly related to skin hydration and inversely related to the development of the stratum corneum. Preterm neonates have an extremely undeveloped (thinner) stratum corneum. This puts them at significantly increased risk for toxicity with exposure to topical agents like hexachlorophene (seizures and neurotoxicity poisoning), povidone-iodine (thyroid dysfunction), corticosteroids (glaucoma, skin thinning), alcohol-containing products (poisoning), and polymixin (ototoxicity). Although the porous skin "tightens up" soon after birth, pediatric patients continue to absorb medications more rapidly than adults due to increased cutaneous perfusion and increased body surface area relative to weight. Even common topical products can produce systemic toxicity, for example use of hydrocortisone containing diaper rash products can produce suppression of the hypothalamus-pituitary-adrenal six when used for 2 weeks or more. To safely use a product such as povidone-iodine solution for a procedure such as a circumcision, a 10% solution should be applied to the affected area before surgery and then removed as soon as the circumcision had been completed, within 5 to 10 minutes.

• Albuterol is frequently prescribed for acute and or chronic management of bronchospasm in asthma or bronchitis. Albuterol may be administered by aerosol (inhaler) in children ≥ 4 years of age if used with a spacer (with or without a mask) and if the child is able to demonstrate appropriate technique with the inhaler. When pediatric patients are having acute problems with bronchospasm the albuterol is frequently administered via nebulization or oral solution. For children 2 to 12 years of age, nebulizer solution dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), but are frequently rounded to increments that match available products (see table below). Dosing should not exceed 10 mg (4 vials) in 24 hours.

When writing orders or prescriptions for albuterol it is important to clarify the route of administration (oral, inhaler, or via nebulization). When ordering nebulized solution it is important to clarify the concentration or intended dose per nebulization. When writing a prescription for outpatients also include intended duration of therapy and quantity of vials to be dispensed. They come in boxes of 25, 30, or 60 doses. The pharmacy will dispense the box with the quantity closest to the prescription.

Neonatal and albumin also have a

a lower affinity for many drugs. This is especially true for neonates, where significant concentrations of fetal albumin may persist.

Albumin and α-1 acid glycoprotein are the proteins most responsible for binding

acidic and basic drugs, respectively.

Transport of bile acids into the gastrointestinal lumen and pancreatic enzyme production are

also reduced, further altering the absorption of pH-sensitive drugs and reducing enterohepatic recirculation.

Potential side effects of topical steroids include local effects and systemic effects such as:

bacterial or fungal skin infections contact dermatitis skin atrophy rosacea aggravation or induction hyper or hypopigmentation striae telangiectasia hypothalamic-pituitary-adrenal suppression delayed wound healing easy bruising hyperglycemia hypertension hypertrichosis ocular changes (cataracts, glaucoma)

In pediatric patients, the apparent volume of distribution (Vd) is normalized based on

body weight and is measured in L/kg.

Benzodiazepine

cognitive

Gastric emptying time is

delayed and intestinal transit time is prolonged at birth, but both quickly increase within the first few days of life because contractions in the stomach become more coordinated and intestinal contractions become more frequent, stronger, and sustained. Premature infants have delayed development of normal 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 generally reached by 4 to 8 months of age.

. Pancreatic lipase activity is

detectable by 32 weeks' gestational age, but remains low at birth and throughout the next 2 to 3 months

For medications that undergo extensive first-pass metabolism, the bioavailability may

increase as the blood supply bypasses the liver from the lower rectum. However, due to other factors some have a reduced bioavailability when administered rectally. For example, many drug dosing references recommend a slightly higher rectal acetaminophen dose (10-20 mg/kg) to account for a potentially lower bioavailability

Extracellular fluid and total body water per kilogram of body weight are

increased in neonates and infants, resulting in higher Vd for water-soluble drugs such as aminoglycosides and decreases with age. Therefore, neonates and infants often require higher individualized doses by weight (mg/kg) compared to older children and adolescents to achieve the same therapeutic serum concentrations.

In contrast, some central acting agents (e.g. morphine sulfate, chloral hydrate, phenobarbital) have been associated with

increased toxicity in the neonatal population; one of factors leading to replacement of phenobarbital and chloral hydrate with alternative agents. As mentioned previously, displacement of bilirubin from albumin increases the risk of kernicterus in neonates as are result of this increased permeability.

Drug metabolism is the process by which medications are altered with the intent of

increasing water-solubility and enhancing drug clearance. Most drug metabolites are inactive, but several have therapeutic or toxic effects.

Tubular secretion

is another common mechanism by which many weak organic acids and bases (drugs) are renally eliminated. The development of this system lags behind that of glomerular filtration due to underdevelopment of the proximal convoluted tubule in newborns relative to the glomerulus. At birth, a full term neonate has approximately 20% of the secretory capacity of an adult. This capacity increases dramatically during the first 2 months to about 60% of adult values and adult capacity is approached at approximately 7-10 month of age. Examples:

Amylase activity

is minimal at birth and remains low until the third month of life.

Renal function should be closely monitored in children and drug doses adjusted accordingly. In the first days after birth serum creatinine values reflect maternal creatinine transferred through the placenta and may appear falsely elevated. After the first week, serum creatinine values are

low as a result of less muscle mass, especially in premature neonates. Urine output is often used as a measure of renal function.in this population. Diaper weights can be used to estimate output. Values greater than 1 mL/kg/hour are considered adequate. After infancy, serum creatinine may be used to estimate clearance. The Cockcroft -Gault and MDRD (Modification of Diet in Renal Disease) equations used for adults should not be used for evaluating patients younger than 18 years of age. The National Kidney Disease Education Program recommends that the best equation for estimating glomerular filtration rate (GFR) from serum creatinine in children is the bedside isotope dilution mass spectroscopy (IDMS) Schwartz equation. [note that some resources show CrCl and others show GFR on the left hand of the equation]

For example, phenytoin is clearly affected by these factors. Phenytoin is about 90% protein bound in the adult population. That leaves approximately 10% of the drug available for activity. In other words, an adult with a serum phenytoin concentration of 20 mg/L should have 2 mg/L existing as free (active), unbound drug in serum. A similar total serum phenytoin concentration in a neonate would be associated with a

much larger free fraction of drug (>2 mg/L); a phenytoin concentration of 20 mg/L in adults is at the upper limit of the therapeutic range and in a neonate is more likely to produce toxicity.

• Introduction of technological advances such as computer physician order entry (CPOE) systems and electronic health records (EHRs) may minimize some medication errors. Whether handwritten or typed the following recommendations should still be considered for prescriptions:

o For oral liquid formulations, order/write dose in mg rather than volume to be administered. Recognize that different concentrations may be available, therefore, write the dose in mg rather than volume. (see antibiotic examples) o Double check decimal placements. Tenfold dosing errors involve misplacement of decimal. o Use zeroes before a decimal point in fractions (e.g. 0.3 mL or 0.5 mg) o Avoid zeroes after whole numbers (e.g. use 30 mg instead of 30.0 mg) o Write out the word units instead of using abbreviation (e.g. u) o For prescription writing/ordering, provide adequate information to allow the pharmacist to be able to double check drug and dose calculations and appropriately counsel the parents, caregiver, or patient: Include drug name, dosage, formulation, route, and duration of treatment. Duration of treatment is important especially for antibiotics or other therapies when symptoms resolve early in therapy. Parents may prematurely stop therapy if not told a specific duration of therapy. Include patient weight and age Include pertinent allergy information Consider the number of doses and palatability. Order an adequate quantity of the medication to complete the desired duration of therapy.

Ensure that practical directions accompany medication administration directions for the parents and caregivers:

o For orally administered liquid formulations, (in addition to directions above) also make sure the parent or caregiver receives instructions about the volume per dose to be administered. For example, although a medication order should clearly state themg per dose for dispensing purposes, the caregiver must receive the dosing directions in volume or # of tablets that make up the dose.

It is crucial to verify accurate weight, height and age for dosing calculations. Consistent units of measurement in reporting patient weight (kg), height (cm), and age (weeks and years) should be used. Double check ALL aspects of dosage calculations:

o Is the dose based on body weight or BSA? o Have you converted lb to kg? Once converted - weight should ONLY be expressed in kg. o Continue to reweigh patients, update, and adjust weight used in dose calculations, especially in neonatal patients; the impact of weight changes is greater in neonates o Dosing units such as mg/kg, mcg/kg, mEq/kg, or units per kg should be used accurately o For combination drug products use the right component for the dose calculation (dose of sulfamethoxazole/trimethoprim is calculated based on the trimethoprim component) o Double check conversions: g, mg, micrograms o Double check decimal placements. Misplacements of decimals result in ten -fold dosing errors o Check the calculated dose against those for comparable weight and age recommendations

There is a misconception that pediatric patients may be treated as "small adults" and drug doses are scaled to their smaller size. Instead, there are multiple factors to consider when selecting and providing drug therapy for patients in the pediatric population. Pediatric patients differ from adults and even differ between pediatric age groups in many aspects, such as

organ function development. This in turn affects dosing, efficacy, and safety of drug therapy. For certain diseases the preferred drug therapy for pediatric patients may vary from what would be selected for an adult patient.

There is one example when, the delay in systemic absorption after IM injection in the neonate is used as an advantage for the administration of

phytonadione (vitamin K) after birth. The delayed absorption from muscle results in a depot like effect, providing a slow release of the drug into the systemic circulation until the infant's dietary intake is adequate to maintain necessary vitamin K serum concentrations. The single IM injection of vitamin K protects from bleeding until approximately one month of age, when the infant would be taking in adequate concentrations through h breast milk or infant formula.

Emollients and diaper rash products are another common class of topically applied pediatric medications. The emollient with the least likelihood of contact dermatitis is

pure white petrolatum. Aquaphor™ is a more expensive, but acceptable, alternative. Zinc oxide is a safe, efficacious, commonly prescribed medication for diaper rash. A paste formulation may be advantageous with diarrhea. When candidiasis is present, a prescription for a topical antifungal agent (azole) may be necessary. In general, the components of infant skincare products that lead to contact dermatitis are: fragrances, neomycin, nickel, thimerosal, and methanol.

Body Water:

r: Figure 1 shows the changes in body water composition that occur throughout development. For example, water comprises about 80% - 85% of a typical premature infant's body weight. At 1 year, the percentage of total body water has decreased significantly and approaches that of the average adult (55-60%). However, the ratio of intracellular to extracellular fluid is nearly equal in this population. As you can see from Figure 1, as we move through infancy and childhood into adulthood, the ratio of intracellular fluid increases relative to that of extracellular fluid.

For drugs absorbed through passive diffusion,

reduced splanchnic blood flow during the first weeks of life can reduce the rate and extent of absorption by altering concentration gradients across the intestinal villi. Reduction in blood flow may also place neonates at risk for damage to the gut lining from hyperosmolar drug formulations. As a result, many institutions delay use of the enteral route for drug administration until the patient is receiving at least one-quarter to half of their nutritional needs through enteral feedings. This allows dilution of drug doses and may reduce the risk for mucosal damage. Lower levels of metabolic enzyme activity in the intestine may reduce first-pass metabolism of drugs given enterally. For example, 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 in the older patients. Intestinal enzymatic activity does not approach adult values until 2 to 3 years of age.

Gastric acid output increases during

the first 1 to 2 weeks of life, but only reaches adult values at 2 to 3 years of age.