pediatrics lecture 1 (introduction & developmental pharmacology) (8!3!2011) dr.m.hesham

7/29/2019 Pediatrics Lecture 1 (Introduction & Developmental Pharmacology) (8!3!2011) Dr.M.hesham

1/11

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 andpharmacodynamics in infants and childrenFrom 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.

1


2/11

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 age-

dependent 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 whocannot 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

2


3/11

when intravenous 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 childrenhave lower tidal volumes and increased respiratory rates leading to

reduced drug delivery and absorption in the lungs. Studies have shownthat 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.

3


4/11

- 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 infantshave 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. Thetwo 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 areprescribed 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

4


5/11

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 to0.8 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 aminoglycosides 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 drugsthat 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.

5


6/11

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 reflectsthe 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 ininfants 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

6


7/11

phenobarbitone, sedation of hyperactive children with amphetamine)

are as yet unexplained. Augmented responses to warfarinin

prepubertal patients occur at similar plasma concentrations as in

adults, implying a pharmacodynamic mechanism.

Some adverse effects causelifelong effects as a result of toxicityoccurring 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 age-dependent 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 Therapy1) 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 moderate-

to-severe renal failure.

7


8/11

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 ofdelivery 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 thepatients 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

8


9/11

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 diazepamis particularly

valuable in the treatment of status epilepticus when intravenous

access is often difficult. Rectal diazepammay 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.

9


10/11

4) Dosage

Body weightbased dosing is the most common method for pediatric

dosing. A total daily dose, milligrams per kilogram per day

(mg/kg/day), is divided by the dosing interval to calculate each

individual dose. Analgesics, antipyretics, and emergency drugs areoften 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 calculationsrequired 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.

10


11/11

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.

11

pediatrics lecture 1 (introduction & developmental pharmacology) (8!3!2011) dr.m.hesham

Documents