Introduction and Developmental Pharmacology

Who are pediatric patients? Definitions

Newborn or neonate: < 1 month old

Preterm or premature: < 37 weeks gestation Term: 37 weeks gestation Infant: < 1 year old Child: 1-12 years Adolescent: 12-18 years

Pediatrics as a unique population

There are limited data on the pharmacokinetics, pharmacodynamics,

efficacy, and safety of drugs in infants and children Only one fourth of the drugs approved by the Food and Drug Administration (FDA) have indications specific for use in the pediatric population. Dosing (mg/kg or mg/m2) frequently based on adult data

Characteristics of pharmacokinetics and pharmacodynamics in infants and children

From the perspective of pharmacotherapy, the process of development and growth in childhood represents an unstable and dynamic condition. The immaturity of the pediatric patient and the continuous state of development of body and organ functions influence both drug effects and drug disposition. Age-related differences in drug pharmacokinetics and pharmacodynamics occur throughout childhood and account for many of the differences between drug doses at various stages of childhood. Therefore, children should not be considered as scaled down adults as the differences in dose are not purely dependent upon body mass. Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and infants.

Newborns require special consideration because they lack many of the protective mechanisms of older children and adults. Their skin is thin and permeable. Their stomachs lack acid. Their lungs lack much of the mucus barrier. After delivery, they are only dependent on their own drug metabolizing enzymes. When the infant is 1 year old, drug absorption, distribution and excretion are in general similar to that of an adult. The exception is hepatic metabolism where there is agedependent increase in hepatic clearance compared to adults.

Developmental Pharmacokinetics Drug Absorption

Oral Drug Absorption Changes in the intraluminal pH in different segments of the gastrointestinal tract can directly affect both the stability and the degree of ionization of a drug, thus influencing the relative amount of drug available for absorption. During the neonatal period, intragastric pH is relatively elevated (greater than 4) consequent to reductions in both basal acid output and the total volume of gastric secretions. Thus, oral administration of acid-labile compounds such as penicillin G produces greater bioavailability in neonates than in older infants and children. In contrast, drugs that are weak acids, such as phenobarbital, may require larger oral doses in the very young in order to achieve therapeutic plasma levels. The gastric emptying time is delayed in both preterm and full-term neonates during the first 24 hours of life. Reduced activity of bile acids, lipase, alpha-amylase, and protease continues until approximately 4 months of age. Changes in the intestinal microflora during infancy are suggested by the finding that the urinary excretion of metabolites such as digoxin reduction products produced by bacterial (enzyme) degradation is age dependent. Rectal Absorption The rectal route of administration is usually reserved for patients who cannot tolerate oral drugs or who lack intravenous access. In rectal administration, the drug is absorbed by the hemorrhoidal veins, which are not part of the portal circulation, therefore avoiding first-pass hepatic elimination. Unfortunately, most drugs administered by this route are erratically and incompletely absorbed. The rectal administration of diazepam (Valium) has been used to control seizures
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when intra- venous access could not be quickly established in infants or children with status epilepticus Intramuscular Drug Absorption Neonates have decreased muscle mass, and their limited muscle activity decreases blood flow to and from the muscle. Collectively, these factors produce erratic and poor intramuscular drug absorption. Percutaneous Drug Absorption Enhanced percutaneous absorption during infancy may be accounted for, in part, by the presence of a thinner stratum corneum in the preterm neonate and by the greater extent of cutaneous perfusion and hydration of the epidermis (relative to adults) throughout childhood. The ratio of total body surface area to body weight in infants and young children far exceeds that in adults. Thus, the relative systemic exposure of infants and children to topically applied drugs (e.g., corticosteroids, antihistamines, and antiseptics) may exceed that in adults, with consequent toxic effects in some instances. Pulmonary Absorption Aerosolized drug delivery to the lungs continues to be a favorite technique in many respiratory disorders, such as asthma. Factors affecting drug deposition in the lungs include particle size, lipid solubility, protein binding, drug metabolism in the lungs, and mucociliary transport. Besides drug considerations, pediatric characteristics also affect aerosol drug delivery. Infants and children have lower tidal volumes and increased respiratory rates leading to reduced drug delivery and absorption in the lungs. Studies have shown that less than 2% of aerosolized drugs are deposited in young infants and toddlers. Therefore, adult dosing may be necessary to counteract these effects.

Drug Distribution
Six factors affect drug distribution in the pediatric population: vascular perfusion, body composition, tissue binding characteristics, physicochemical properties of the drug, plasma protein binding, and route of administration. During the neonatal period, most of these factors are significantly different from those in the adult population, while children and adolescents are very similar to or the same as adults.
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- Body Composition Neonates have increased total body water (75% to 80%) with decreased fat compared with adults, resulting in a higher water-to-lipid ratio. After the neonatal period, fat increases and total body water decreases steadily until puberty. For instance, neonates and infants have increased total body and extracellular water, creating a larger volume of distribution and affecting the pharmacokinetics of some water soluble drugs, such as aminoglycoside. The larger volume, in turn, requires administering a larger milligram-per-kilogram dose of aminoglycoside to neonates and infants than to adults.

- Plasma Protein Binding A reduction in the quantity of total plasma proteins (including albumin) in the neonate and young infant increases the free fraction of drug, thereby influencing the availability of the active moiety. This means that decreased protein binding in neonate and infant leads to more drugs at the receptor site and increased effect of the drug.

Drug metabolism
Clearance of many drugs is mainly reliant on hepatic metabolism. The two phases of drug metabolism in the liver are the oxidation, reduction, and hydrolysis reactions (phase I) and conjugation reactions (phase II). Age-related changes in metabolism affect how drugs are broken down or trans- formed in pediatric patients and how certain metabolic enzymes are activated. Phase I and II reactions are delayed in neonates, infants, and young children, with consequential drug toxicities. P450 cytochrome (CYP) is the most important component of phase I drug metabolism. The metabolism of caffeine and theophylline, the prototypic substrate for CYP1A2, is reduced at birth. To maintain therapeutic serum theophylline concentrations, smaller doses are prescribed and administered less frequently in neonates than in older infants and children. In adults, acetaminophen (a substrate for glucuronosyltransferase) is metabolized by a phase II glucuronidation reaction. In neonates and

infants, however, this metabolic pathway is deficient. As a result, acetaminophen metabolism is shifted to sulfate conjugation.

Drug Elimination
Almost all drugs and their metabolites are excreted through the kidneys. The glomerular filtration rate (GFR) may be as low as 0.6 to 0.8 mL/min per 1.73 m2 in preterm infants and approximately 2 to 4 mL/min per 1.73 m2 in term infants. The glomerular filtration rate increases quickly during the first 2 weeks of postnatal life. The processes of glomerular filtration, tubular secretion, and tubular reabsorption determine the efficiency of renal excretion. These processes may not develop fully for several weeks to 1 year after birth. Because the elimination of amino- glycosides is directly related to the GFR, aminoglycosides have a longer half-life in neonates and infants, thus requiring a longer dosing interval than in adults. Thus, for drugs that are primarily eliminated by the kidney, clinicians must individualize treatment regimens in an age-appropriate fashion that reflects both maturational and treatment-associated changes in kidney function.

Developmental Pharmacodynamics
It means the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. Few studies exploring developmental PD reflects the ethical and practical constraints of conducting studies in children. GABAA receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the opioid receptor. Age-related pharmacodynamic differences have also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. Also, the maintenance dose of digoxin is substantially higher in infants than in adults. This is explained by a lower binding affinity of receptors in the myocardium for digoxin and increased digoxin binding sites on neonatal erythrocytes compared with adult erythrocytes. Moreover, the apparently paradoxical effects of some drugs (e.g. hyperkinesia with
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phenobarbitone, sedation of hyperactive children with amphetamine) are as yet unexplained. Augmented responses to warfarin in prepubertal patients occur at similar plasma concentrations as in adults, implying a pharmacodynamic mechanism. Some adverse effects cause lifelong effects as a result of toxicity occurring at a sensitive point in development (a critical window) during fetal or neonatal life (programming) as with thalidomide/ phocomelia or hypothyroid drugs/congenital hypothyroidism.

Developmental Pharmacogenomics
Some genes are expressed much more in early life than in adults and such gene switching could give rise to a situation where a drug was effective at one age but not another. Apparent pharmacogenetic determinants of the action of a drug may contribute to the agedependent differences in the response to treatment of children with certain well-defined diseases (e.g., asthma and leukemia) and to the likelihood of severe adverse events (e.g., the hepatotoxicity of valproic acid is increased in young infants).

Factors Affecting Pediatric Drug Therapy

1) Concomitant diseases Because most drugs are either metabolized by the liver or eliminated by the kidney, hepatic and renal diseases are expected to decrease the dosage requirements in patients. Because the liver is the main organ for drug metabolism, drug clearance usually is decreased in patients with hepatic disease. Renal failure decreases the dosage requirement of drugs eliminated by the kidney. Serum drug concentrations should be monitored for drugs with narrow therapeutic indices and eliminated largely by the kidney (e.g., aminoglycosides and vancomycin) to optimize therapy in pediatric patients with renal dysfunction. For drugs with wide therapeutic ranges (e.g., penicillins and cephalosporins), dosage adjustment may be necessary only in patients with moderateto-severe renal failure.
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2) Routes of Administration Oral When prescribing or administering oral drugs for pediatric patients, the caregiver needs to consider not only the drugs flavor and ease of delivery but the frequency of administration, dosage form, and inactive ingredients, such as alcohol and sugar. A liquid dosage form is preferred for most pediatric patients. To ensure the accuracy of each dose administered, the drug should be measured and then administered with an oral syringe or a calibrated drug cup. If the patient is an infant, the head should be raised to prevent aspiration of the drug. Applying gentle downward pressure on the chin with a thumb helps open the patients mouth. If a syringe is used, the tip of the syringe should be placed in the pocket between the patients cheek and gum. However, a drug should never be mixed with the contents of a babys bottle because the correct dose will not be received if the infant does not consume the full contents of the bottle. In addition, a drugnutrient interaction may occur if a drug is mixed with formula. A classic example of a drugnutrient interaction is the significant reduction of oral phenytoin absorption after concurrent administration with an enteral feeding formula.

Buccal Drugs may be absorbed rapidly from the buccal cavity (the cheek pouch, melt technology, gels , sprays ) e.g. midazolam for seizures. Nasogastric/gastrostomy For cases of unconsciousness, or difficulty swallowing Intranasal Examples are desmopressin, midazolam, insulin Rectal Toddlers being toilet trained, especially children experiencing stress or difficulty, often resist the rectal administration of drugs. The best
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approach to reducing anxiety and increasing cooperation is to spend time explaining the procedure and to reassure the child that giving drugs by this route will not hurt. Rectal diazepam is particularly valuable in the treatment of status epilepticus when intravenous access is often difficult. Rectal diazepam may also be administered by parents. Rectal administration should also be considered if the child is vomiting. Parenteral The use of topical anesthetics can minimize the pain associated with injections. The optimal site for intramuscular administration depends on the patients age. In children younger than 3 years of age, the vastus lateralis (outer thigh) is the preferred site, whereas the gluteus (buttock) or ventrogluteal (hip) area is preferred in older children. When administering an intravenous drug, it is important to check the compatibility of the drug with all other drugs administered through the same catheter or intravenous tubing. Moreover, more problems with intravenous route in pediatrics includes difficulties to get the intravenous access, possible fluid overload, and lack of suitable pediatric formulations leading to increased risk of medication errors. Pulmonary Nebulizers, metered-dose inhalers (MDIs), and dry powder inhalers (DPIs) can be used to deliver bronchodilators, aminoglycosides, and corticosteroids. Nebulized drugs are often used in infants and young children. MDIs require coordination between actuation and inhalation; this is difficult in any age group, so a tube spacer is recommended for children less than 8 years old and a spacer connected to a face mask for children less than 4 years old. 3) Frequency The frequency of dosing depends primarily on the drugs pharmacokinetic profile (ie, a longer half-life results in less frequent dosing intervals). To improve adherence to a drug regimen, especially in pediatric patients, the drug better to be administered once or twice daily at most. Effective treatment of acute otitis media may imply the use of once-a-day antibiotics.
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4) Dosage Body weightbased dosing is the most common method for pediatric dosing. A total daily dose, milligrams per kilo- gram per day (mg/kg/day), is divided by the dosing interval to calculate each individual dose. Analgesics, antipyretics, and emergency drugs are often administered on a dose-by- dose method; as such, the recommended pediatric dose is reported as milligrams per kilogram per dose (mg/kg/dose). The starting or maximum doses for pediatric intravenous infusions are usually reported as micrograms per kilogram per minute (mcg/kg/minute) or micrograms per kilogram per hour (mcg/kg/hour). Drug dosages based on a patients BSA are usually reserved for antineoplastic agents or critically ill patients. Dosages of several drugs, including syrup of ipecac and kaolin (Kaopectate), are based on age. 5) Adverse effects Relatively few studies have been conducted to assess the risks versus the benefits of drug therapy in the pediatric population. The major limiting factor to using any fluoroquinolone in pediatrics is the risk of severe degenerative arthropathy, which was reported in studies of ciprofloxacin use in animals. Certain adverse effects may not be detected until decades after treatment. For example, secondary cancers, growth retardation, hypogonadism, and sterility have all been reported as late adverse effects associated with certain antineoplastic therapies. Inhaled and intranasal corticosteroids may decrease growth velocity. 6) Medication safety Healthcare professionals have a responsibility for creating a safe medication environment and reducing risk to a vulnerable pediatric population. The vast majority of medical errors that cause harm to patients are preventable. Pediatric medication errors commonly occur at the medication ordering step because of the multiple calculations required for weight-based dosing and the adjustments needed for providing therapy to the developing pediatric patient. Among drug administrationrelated errors, wrong dose, wrong technique, and wrong drug are the three most common errors and may be related to an inability to access pediatric drug information.
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Risk-reduction strategies include placing a clinical pharmacist on pediatric wards in hospitals, simplifying the medication-use system, ordering standardized concentrations and doses, implementing computerized physician order-entry systems with dose range checking, dispensing pharmacy-prepared/ready-to-administer doses, standardizing infusion equipment, using smart infusion pumps, using bar-coded medications and bar-coding systems that check the medication at the point of care, and implementing computerized adverse event detection systems. American Association of Pediatrics (AAP) recommendations For reducing medication errors: Maintain an up-to-date patient allergy profile. Confirm the validity of a patients weight for medications that are dosed by body weight (or body surface area [BSA] for medications dosed by BSA). State specific dosage strengths or formulation. Do not use abbreviations for drug names or patient instructions. Avoid using abbreviations for dosage units. Use a zero before a decimal point. Avoid a zero after a decimal point.

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