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Drug therapy and children.

IT IS generally understood that children are not just "miniature men and women" when it comes to disease and drug therapy, and managing childhood illness requires more than merely reducing the adult dose of a medication. However, maturation and growth from infancy to adolescence are variable and nonlinear processes: estimating the dose and effects of medications for an individual child is a complex undertaking. An understanding of developmental variations throughout childhood in the way drugs are handled by the body, and of the differences in responses to drugs between children and adults, can enhance the provision of best care to our paediatric clients.



AFTER READING this article and completing the online learning activities, you should be able to:

* Describe the impact of developmental differences on the effect of drugs on the body (pharmacodynamics) and of the handling of drugs by the body (pharmacokinetics).

* Discuss barriers to effective drug therapy for the paediatric population.

* Compare various methods for determining drug dosage in infants and children.


The paediatric population encompasses preterm infants through to adolescents and young adults. This age range is divided variously by different organisations; however the International Conference on Harmonisation (ICH) has put forward the following categories for reference during paediatric drug development: (1)

* Preterm newborns: less than 36 weeks' gestation.

* Term newborns: 0 to 27 days old.

* Infants and toddlers: 28 days to two years.

* Children: two to 11 years.

* Adolescents: 11 to 18 years. (The United States Food and Drug Administration guidelines has since defined adolescence as reaching up to 21 years of age. (2))

During these stages, children undergo predictable physical, social, cognitive and emotional development, but within these age groups there is enormous variation in the rate of development. As a result, age-based staging is, at best, a very blunt tool for determining the developmental stage of an individual within the paediatric population.


The way drugs are processed by the body varies considerably with age. Absorption, distribution, metabolism and elimination of drugs depend on physiological processes that change as the body grows and matures. In the paediatric population this can cause clinically significant differences in the amount of drug available for therapeutic effect and the time the drug stays in the body.


All drugs, other than those administered via intravenous injection, must be absorbed across membranes before entering the general circulation. Drugs are most commonly administered to paediatric patients orally or via feeding tube.

The pH, or acidity, of the gastrointestinal (GI) tract varies considerably with age and this can have an effect on the stability and bioavailability of drugs. In neonates, the gastric pH is less acidic than in adults (pH > 4 compared to pH 1-2). This affects acid-labile drugs such as penicillin G--normally a proportion of this drug would be inactivated by acid in the stomach, but in neonates, less drug is destroyed, meaning more is available for absorption and thus a higher dose is received compared to that for older children and adults. (3) Other drugs that rely on an acid environment, eg oral phenobarbital or the antifungal itraconazole, may not be as well absorbed, risking sub-therapeutic dosing.

Gastric emptying rates and intestinal transit times differ considerably between neonates, infants and children. In neonates and infants, gastric emptying time is erratic and slow, not reaching the adult rate until about eight months of age. (4) This causes delayed drug absorption in neonates and infants compared with children and adults, which, for some drugs, may delay the onset of action.

Rapid intestinal transit times in neonates, infants and young children mean reduced contact time for drugs which are mainly absorbed through the surface of the small intestine. Sustained release formulations, or drugs that are poorly absorbed even under normal (adult) conditions, will be less well absorbed, with the risk of sub-therapeutic plasma concentrations. This is compounded by developmental differences in babies and young children, such as reduced presence of pancreatic enzymes and intestinal flora and erratic blood flow to the gut, and when children have diarrhoea.

Erratic blood flow also affects absorption of medications administered via rectal, intramuscular or subcutaneous routes, potentially leading to delays in onset of action. In contrast, transdermal routes of administration, or topically applied medications, will have much greater absorption due to the thinner skin, greater hydration and better blood supply to the epidermis, especially in preterm neonates.3 Neonates, infants and young children also have proportionately more skin (body surface area) to their mass, so the relative exposure to drugs applied transdermally and topically is greater, with increased risk of toxicity. This risk is increased where there is broken or excoriated skin and in the presence of occlusive dressings (including disposable nappies). (5)


Once a drug enters the systemic circulation, it is distributed throughout the body. The more widely a drug is distributed, the lower the concentration in the plasma and (usually) the less drug at the site of action to exert a therapeutic effect.

Some drugs--those with a large molecular size--remain largely within the bloodstream. Examples are anticoagulant drugs such as the heparins. Other drugs distribute only to the plasma and extracellular fluid compartments. These are water-soluble drugs that are lipophobic--they cannot cross the lipid membranes in the body to enter cells or the central nervous system.

In the paediatric population, there are developmental variations in the water content of the body. Preterm infants may have as high as 85 per cent of their total body weight as water, while full-term neonates have 70-75 per cent. This reduces slowly through childhood, reaching adult values of 50-60 per cent in early adolescence. With a higher percentage of the body as water, the distribution of water-soluble drugs is increased, leading to lower plasma concentrations compared to adults on a mg/kg basis. In practice, this means neonates may require higher relative doses of water-soluble drugs, such as the beta-blocker atenolol. (6,7)

In contrast, the proportion of fat to total body weight is much lower than in adults. Preterm neonates may have as little as one per cent of their body weight as fat. Full-term infants have 15 per cent fat, doubling by about six months of age. After this, body fat decreases as the toddler becomes mobile and it fluctuates throughout childhood and adolescence, due to growth requirements and as lean body mass increases, particularly for adolescent boys. By early adulthood, the proportion of fat for the average male is 18-24 per cent, and for females, 25-31 per cent. (6,7)

Low and variable fat content affects the distribution of lipid-soluble drugs in the body. In neonates and infants, the dose of lipid-soluble drugs needs to be reduced proportionally to the adult dose, since there is less fat for these drugs to distribute to, and the concentration in the plasma will remain higher. Examples of lipid-soluble drugs include most anaesthetic agents, fentanyl, benzodiazepines and anti-seizure agents. (7)

Many drugs are transported in the blood bound to plasma proteins. Only unbound (free) drug molecules are able to leave the plasma and travel into the tissues to their sites of action, or into the liver and kidneys for metabolism and excretion. Thus distribution of drugs is affected by the number of plasma proteins available for binding, and by how well the drug molecules are able to bind.

Plasma protein levels are reduced in neonates and infants, not reaching adult values until about one year of age. In adults, abnormal increases in "free" drug molecules can be balanced by the fact that they are also metabolised and excreted in greater numbers. However, in neonates, the liver and kidney are not mature, so clearance of drugs is delayed, and increased "free" drug, due to poor plasma protein binding, can more readily lead to toxicity. In addition, drugs can be displaced from their plasma proteins by other drugs or endogenous substances. Kernicterus can arise when bilirubin is displaced from albumin by drugs such as ibuprofen, ceftriaxone and co-trimoxazole. This is aggravated by the immaturity of the neonatal blood-brain barrier. (6)

In older children and adults, passage of drugs or other water-soluble Substances--such as bilirubin--into the central nervous system (CNS) is prevented by the tight junctions between the cells lining the blood vessels supplying the brain. This barrier is not well developed in the very young, allowing drugs that can affect neural development during this critical growth stage to enter. (3) Thus, medications that are not normally regarded as neurotoxic may become so in this group of patients. At the same time, drugs not normally able to treat CNS infections can be used in this age group as they more readily penetrate to their site of action.


Most drugs are metabolised in the liver, then excreted. Metabolism can inactivate a drug, form active metabolites, or activate a pro-drug. For many drugs, metabolism occurs in two phases involving different sets of enzymes. Phase I metabolism requires a group of enzymes belonging to the cytochrome P450 (CYP) family.

Activity of this system is 70 per cent lower in neonates, compared to adults. Adult values are largely achieved by the age of 10 years. For example, the clearance of intravenous midazolam (metabolised by CYP3A4 and 3A5) rises from 1.2ml/minute/kg in the neonate to 9ml/minute/ kg at three months of age. (3) CYP2D6 metabolises beta-blockers, antiarrhythmic drugs and ondansetron. This enzyme is expressed in the first week of post-natal, life. By four weeks of age, activity is 20 per cent of adult values, increasing to 75 per cent by five years of age. (8)

The subtypes of P450 enzymes present at birth differ from adult forms, which may result in different--and possibly toxic--products of metabolism than those seen in adults. (3,7)

Phase II metabolism has been less studied in children but generally the rate varies by drug. Paracetamol metabolism is delayed in neonates and in children up to 10 years, while that of morphine is 80 per cent of adult values by 12 months. Grey baby syndrome, due to poor phase II metabolism of chloramphenicol, resulting in serious toxicity and death, was one of the first strong indications that deriving dosage merely from an infant's bodyweight is not safe or sufficient practice. (8)

Generally, drug clearance is delayed by two to three times in neonates, compared to adults, but there are some exceptions. Metabolism of drugs such as theophylline and caffeine may exceed adult levels during infancy/toddlerhood and adolescence (depending on gender--girls attain adult (lower) rates of caffeine metabolism earlier than boys). (3,6) In acutely ill children, diminished blood flow to the liver will have an impact on the metabolism of drugs.


Renal elimination of drugs

While the liver inactivates many drugs, some are converted to active metabolites, and others are not metabolised at all so must be excreted in their active form through the kidneys. Any delay in excretion of active drugs or metabolites through the kidneys leads to an increased risk of toxicity. In the neonate and infant, renal excretion is affected by a number of factors: (30

> Blood flow to the kidneys is low at birth (about 12ml/minute) and does not reach adult levels (140ml/minute) until about one year of age.

> Glomerular filtration rate is also low, at 2-4ml/minute, increasing to adult rate (120ml/minute) by six to 12 months of age.

> Tubular secretion of drugs (the route by which many important drugs are excreted) is poorly developed at birth and increases during the first year.

Drugs such as aminoglycoside antibiotics (eg gentamicin) that are renally excreted must be administered at extended dosing intervals and carefully monitored. Tubular secretion is the main route of elimination for diuretics, nonsteroidal anti-inflammatories, methotrexate and penicillins. (7)


The action a drug has on the body depends on its delivery to the site of action (determined by pharmacokinetics) and its ability to bind to and cause a response in its target receptors. There is evidence that target receptors and enzymes may differ in number and function between children and adults, leading to, for example, greater activity by warfarin in children at the same relative dose, and increased sedation from midazolam. However, there is insufficient human research evidence to define receptor differences conclusively. (19)

Measurement of responses to drugs in paediatric patients can be problematic--eg pain assessment--meaning that extrapolation of effects from adults or older children to the very young could be misleading. It cannot be assumed that drugs meant for adult conditions can effectively treat diseases unique to neonates or children. But lack of knowledge about the actions of drugs in children, due to poor inclusion in research trials, means often having to extrapolate from adult data. (1)


Before the 1970s, children were routinely excluded from drug trials due to concerns about their vulnerability and inability to provide truly informed consent. Also, there was little research about physiological development available to support rigorous research. Difficulty recruiting and studying adequate numbers of children to account for variations in age and development was a cost consideration that also deterred pharmaceutical companies. (9)

Lack of trial data meant most times a drug was prescribed for and administered to a paediatric patient, health-care professionals were essentially conducting uncontrolled experiments. Furthermore, being denied access to the full range of drug therapies available to adults was potentially harming children. Both these scenarios could be deemed unethical. (9) A further concern was the lack of appropriate paediatric formulations of drugs, and knowledge about how these might affect the drugs' pharmacokinetics.

In the last three decades, the United States Food and Drug Administration has encouraged pharmaceutical companies to research drugs in children by extending the patent life of new drugs for an extra six months. They have also required that paediatric data be submitted with all new drug applications, if these have potential to be used in children (the Pediatric Final Rule). The European Medicines Agency implemented similar rules and incentives in 2007. (10) The outcome has been a significant increase in the labelling of drugs with paediatric data, allowing safer drug therapy for children. (9)

Older drugs are not included in this research drive, since pharmaceutical companies gain no profit from researching drugs already out of patent. This leaves a large gap in the paediatric armamentarium unless prescribing is done "off-label". It also means that, potentially, children are being prescribed newer drugs on the market where an older drug may be as safe. The inherent risk is that many adverse effects of drugs are not identified until they have been on the market for a considerable length of time, and administered to many more people than is possible in even the most extensive clinical trials. Warnings were issued in 2004 about the use of selective serotonin reuptake inhibitors (eg fluoxetine) in young patients due to increased tendency to suicide. This class of drugs had been on the market since the late 1980s.

Children comprise only a small percentage of the population, and tend to be healthy. Recruiting sufficient children with the relevant diagnosis for drug trials can be difficult, and active recruitment of children for trials may lead to accusations of exploitation. Furthermore, due to age stratification in the paediatric population, drugs may be researched in only select groups--labelling may then restrict use to that group. Most often, neonates and infants are excluded from research, and labelling disclaimers such as "safety and effectiveness have not been established for children under the age of..." are common.

Drug research is not risk-free, especially with new classes of drugs ones that act by completely novel mechanisms. As a vulnerable group, children require extra protection in terms of consent. There is a degree of difference between obtaining parental permission for a child to participate in research and obtaining fully informed consent from the trial participant. (11)

Children are regarded as a vulnerable group in terms of pharmaceutical research due to concerns about their capacity to make decisions and the influence of external authority figures, as well as social undervaluing of their rights and interests. (12) The principles governing paediatric pharmaceutical research should include:

> Scientific necessity: the trial must be investigating an important scientific or public health problem that concerns the health and welfare of children.

> There must be an appropriate balance of potential benefits and risk of harm.

There must be little or no risk to a child (including discomfort during testing) if there is no direct therapeutic benefit for that child from the research. Children should also not be placed at risk by failure to receive necessary care--the placebo arm of a trial must not be absence of therapy. (120 Predicting it will yield important knowledge is not a sufficient reason for conducting a paediatric clinical trial.

Conditions related to assent and parental consent vary, depending on the degree of perceived risk. Assent by a child must be more than the absence of dissent but is subject to some controversy: definitions of assent, age at which it should be sought, and who should be involved, are all areas of disagreement between experts. More importantly, the resolution process where children and parent disagree and what constitutes true assent remain unresolved.
Box 1. Approved, unapproved
and off-label prescribing

AN AUTHORISED prescribing health professional may
prescribe any drug to any patient under their care (within
that practitioner's scope of practice), whether that drug is
approved for use in this country or not. An unapproved drug
is one that is not licensed for use in New Zealand, although
it may have been licensed for use elsewhere. Often lack of
approval is due to drug companies not wishing to undertake
the expense of gaining consent for marketing and sale
of drugs through an individual country's regulatory regime.

An approved medicine will usually have a Medsafe datasheet
and be monitored for quality, safety and efficacy by
Medsafe. This is not the case for unapproved medicines, although
the New Zealand Formulary may provide information
about some drugs.The Medsafe datasheet contains information
about all approved uses of an approved drug, including
the patient populations, dosages, route of administration
and formulation, and the conditions it is intended to treat.
Any use of the drug outside these published criteria is
considered unapproved use of an approved medication or

Use of unapproved or off-label medicines is subject to
the Health and Disability Commission's Code of Rights.

A prescriber has responsibility to ensure an individual's
treatment meets an appropriate ethical and professional
standard. If offered these medications, a patient has the
right to be fully informed:

* That the medicine is unapproved or being prescribed

* About the standard of evidence used by the practitioner
to support its use for this patient.

* About any safety concerns about the use of this medicine.

* Whether the use of this medicine is part of a clinical

Consent can be verbal or written, but should be written
where evidence of efficacy or safety is minimal or equivocal,
or if the drug is part of a clinical trial. The decision to
prescribe should be clearly documented with rationale and
patient consent in the clinical notes. As with all medicines
(approved or unapproved), an individual risk/benefit analysis
should be performed before prescribing.

For further reading, see Medsafe Compliance: Use of
unapproved medicines and unapproved use of medicines, at, and the Best
Practice Advocacy Centre's (BPAC) Unapproved medicines
and unapproved uses of medicines: keeping prescribers
and patients safe, at

Lack of evidence for drug use in the paediatric population means that prescribers are frequently left to extrapolate from adult research data in terms of safety, efficacy, indications for treatment, and dose. Thus prescribing is based on trial and error, relying on the judgement of (hopefully) expert practitioners, and is frequently categorised as unapproved or "off-label" use of the drugs.


Up to one third of drugs prescribed for children in the community and 80 per cent in hospital are categorised as "off-label" or unapproved/ unauthorised (see Box 1, facing page). (13) There is evidence of increased harm to children from off-label and unapproved use of medications--up to two to five times increased risk--although this is probably underreported. (14)

In 2010, the European Medicines Agency published a report documenting the use of drugs in the paediatric populations of Europe that were unauthorised or off-label. The main therapeutic classes involved were antiarrhythmics, antihypertensives (including renin-angiotensin inhibitors and beta-blockers), proton pump inhibitors, asthma drugs, antidepressants, contraceptives (for adolescents) and antibiotics (for neonates and infants). (15)

In New Zealand, the Formulary for Children endeavours to provide approval status for medicines listed, but this information is not always available. (16) Unapproved medicines are labelled "section 29", referring to the appropriate section of the Medicines Act.

To illustrate the list above, antiarrhythmics listed in the Formulary for Children include adenosine and amiodorone, both of which are not approved for use, flecainide which is only approved for use in children over 12 years (and the oral liquid is an unapproved medicine) and lidocaine, which is approved for use. Of the eight beta-blockers listed, only one is approved for use in children less than 18 years of age.


Formulations of drugs contain other ingredients in addition to the active drug. Known as excipients, they are often substances used to deliver the drug in a useable form. Excipients have caused a series of disasters in paediatric drug therapy over the past 70 years.

The first occurred in the 1930s when an American drug manufacturer added diethylene glycol (DEG)--an odourless, sweet solvent--to an antibiotic elixir. As a result, 105 people died, 34 of them children. (9) DEG is used in the manufacture of plasticizers, to maintain moisture in tobacco and as a component of brake fluid and other lubricants. Ingested even in very low doses, it triggers renal, liver and neurological damage, leading to death. (17)

Glycerol and propylene glycol are much safer alternatives for pharmaceutical use, but these are easily contaminated with DEG, sometimes deliberately so in cheaper manufacturing processes.

Since the 1930s, there have been a number of outbreaks of DEG poisoning causing the deaths of children: South Africa in 1969--seven children died from an over-the-counter sedative mixture; Nigeria and Bangladesh, 1990--almost 400 children died, in separate incidents, after being administered contaminated paracetamol elixir; Nigeria, 2008-84 children died after DEG-contaminated teething mixture was supplied by a Nigerian manufacturer. (17)

In Haiti in the mid 1990s, 99 children died after being administered paracetamol preparations, and in Panama in 2006, 219 largely older victims died after taking a cough elixir. In both cases, the contaminants were traced back to a manufacturer in China but Chinese authorities were slow to act. DEG was also found to be present in high amounts in toothpastes worldwide that had originated from China in 2007, although there were no reported ill-effects. (17)

In 1982, benzyl alcohol--a preservative used in heparin flushes--was found to be responsible for neonatal gasping syndrome and the deaths of 16 preterm neonates in the US. In older children and adults, this chemical is metabolised to a non-toxic product, but in neonates the immature liver metabolises benzyl alcohol to the highly toxic benzoic acid. (9)


The arbitrary division of paediatric populations into groups by age (neonate, infant, child, adolescent) assumes a linear relationship between age, size and functional maturity. (3) But as discussed earlier, this is not the case. For many drugs, safe dosing in older children can be extrapolated from adult doses based on age and/or weight--this is particularly true for medications with low toxicity risk. Weight-based calculations become more problematic with obese children, and often dosing is determined by ideal weight-for-height calculations. In all cases, weight-based dose calculations should not exceed adult dose. (16,18)

Body surface area (BSA) calculations are frequently used to estimate dose for young children. The height and weight of the child are used to determine BSA compared to the average adult, and the dose is reduced proportionately. This method assumes a relationship between organ maturity and body size, which may not be accurate.

Also, formulae for calculating BSA are complex and may be inaccurate; they are difficult to use in emergency situations, and they have a tendency to overdose infants and neonates. (18)

For drugs with a greater risk of toxicity and for the very young, where pharmacokinetic considerations play a major role in dose determination, the most reliable way to ensure correct dosing is through measuring the plasma drug concentration. This is not always practical, and comes with the added risk of blood volume depletion where testing is frequent in neonates or infants. Complex algorithms can be used to determine dosing, but this relies on incomplete data about pharmacokinetic and pharmacodynamic differences in all stages of development. In addition, the more complex a dosing calculation regime, the less likely it is to be used in clinical practice and the greater the risk of prescribing errors. (18)


Use of medications in children is complex. Children cannot be considered mini-adults in terms of either their responses to drugs or the course of their illnesses. Nurses are responsible for the safe and timely administration of drug therapy to children in their care. An understanding of developmental differences in the way drugs are handled by paediatric patients, and in their responses to these drugs, enables us to identify early potential problems caused by drug therapy.

* References for this article can be found at

Georgina Casey, RN, BSc, PGDipSri, MPhil (nursing), is the director of She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
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Title Annotation:CPD + nurses
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Geographic Code:8NEWZ
Date:Aug 1, 2014
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