Medication use in children

Transcription

1 Medication use in children Children make up a significant proportion of healthcare consumers in Australia, accounting for approximately 15% of all general practice consultations. The burden of disease in children is significant, with almost two in five children having at least one chronic condition. Despite this, the use of medication in younger patients is sometimes overlooked due to a lack of clinical studies and guidelines, or a perception that children are generally healthy and not users of chronic or complex medication regimens. Children are a complicated population for prescribing medications. They are continually changing with respect to growth, psychosocial development, pharmacodynamic response, and pharmacokinetics. Objectives: After completing this activity, pharmacists should be able to: Recognise factors impacting on safely selecting and using medications in children Describe the issues surrounding the pharmacokinetic differences between paediatric patients and adults Discuss the importance of prescribing guidelines when using medications in children. This activity has been accredited for 1 hour of Group One CPD (1 CPD Credit) that may be converted to 2 Group Two CPD Credits upon successful completion of the corresponding assessment for inclusion on an individual pharmacist's CPD Record. Accreditation number: A1311AP0. Successful completion of this activity is demonstrated by answering four of the five multiple choice questions correctly. The competency standards addressed by this activity include (but may not be limited to) 4.2.2, 4.2.3, 6.1.1, 6.1.2, 6.1.3, 6.2.1, 6.2.2, 7.1.2, Author: Ella van Tienan BPharm (Hons) PhD MPS AACPA Ella is currently a lecturer in pharmacokinetics at UTas, working as a consultant pharmacist performing medication reviews in residential facilities and HMRs, and also locuming from time to time in community pharmacy. And worth noting for this particular CPD the mother of a todder. AusPharm gratefully acknowledges the financial support provided by the sponsors of our CPD program, MIMS

2 Medication use in children Introduction The paediatric population represents a spectrum of different physiologies, and children should not be treated as miniature men and women (Abraham Jacobi, ). Children make up a significant proportion of healthcare consumers in Australia, accounting for approximately 15% of all general practice consultations.(1) The burden of disease in children is significant, with almost two in five children having at least one chronic condition.(2) Despite this, the use of medication in younger patients is sometimes overlooked due to a lack of clinical studies and guidelines, or a perception that children are generally healthy and not users of chronic or complex medication regimens. Children are a complicated population for prescribing medications. They are continually changing with respect to growth, psychosocial development, pharmacodynamic response, and pharmacokinetics. The paediatric population can be classified as: - preterm newborn infants - term newborn infants or neonates (0 to 28 days) - infants and toddlers (> 28 days to 23 months) - children (2 to 11 years) - adolescents (12 to 16 to 18 years, depending on the region).(3) Information regarding developmental changes in pharmacodynamics is limited and there are few examples that provide evidence for changes in the response to medications during growth and development.(4) A great deal is known however about the pharmacokinetic changes that occur during development, and it is these changes that primarily influence our approach to dosing medications in paediatric patients. Pharmacokinetic differences between children and adults Pharmacokinetics describes the body s effects on medications, incorporating the processes of absorption, distribution, metabolism and excretion, each of which can be altered by some degree at each developmental stage. A summary of the changes to the pharmacokinetic processes in children is illustrated in Figure 1.

3 Figure 1: Developmental changes in pharmacokinetic parameters that influence medication use in children (Taken from Kearns et al.(4))

4 Absorption Medications administered by any extravascular route must overcome chemical, physical, mechanical, and biological barriers in order to be absorbed. Most drugs are administered orally to children, and absorption from within the gastrointestinal tract may experience variation subject to changes in a number of factors: - gastric acid secretion: changes in the ph of gastric fluids can affect the stability and the degree of ionisation of a drug, influencing the amount of drug available for absorption. The ph of the stomach is elevated and practically basic in neonates and young infants, slowly declining until it reaches adult values at about two years of age.(5, 6) The practical implications of these changes to gastric ph are that acid labile drugs, such as penicillin, will generally have an improved bioavailability in neonates than in older infants and children.(7) In contrast, a small number of weakly acidic drugs, such as phenytoin, will generally have a reduced bioavailability in neonates and may require larger doses to achieve therapeutic levels. - bile salt formation: bile salts play an important role in promoting the solubility and subsequent absorption of lipophilic drugs. Infants under six months old, in particular, have immature biliary function, resulting in poor conjugation and transport of bile salts into the intestinal lumen.(4, 6) This may result in a reduction in the bioavailability of some lipid soluble drugs, such as diazepam. - gastric emptying and intestinal motility: gastric emptying and intestinal motility are the primary determinants of the rate at which drugs are presented to the mucosal surface of the small intestine for absorption. The time of gastric emptying is delayed in the period immediately after birth for both full term and pre-term neonates, approaching adult values within the first 6 8 months of life.(5, 6) Generally, this results in the rate at which most drugs are absorbed being slower in neonates and young infants than in older children.(4) Drugs for which gastric emptying is the rate limiting step are particularly affected. For example, paracetamol reaches peak plasma concentrations after approximately half an hour in adults and children, while the time to maximum concentration for neonates is closer to two hours (Figure 2).(8) The practical implication of this is that the time required to reach maximal plasma drug levels is prolonged in the very young, which may impact the efficacy of drugs required for acute effects, such as antipyretic and analgesic agents when used in the neonatal population. Pharmacists may suggest to caregivers that administration of paracetamol on an empty stomach wherever possible will result in faster therapeutic effects than administration with food, and counsel on the fact that it is likely that it will take longer to observe the benefits of a single dose of paracetamol in young children than would be expected in older children and adults. - first pass metabolism: first pass metabolism refers to the pre-systemic metabolic clearance of a drug, generally by enzymes present in the intestinal lumen or the liver. Expression of some cytochrome P450 (CYP) enzymes, in particular CYP3A4 but others as well, increases with age. The consequence for neonates and children is reduced first-pass metabolism, or pre-systemic clearance of many drugs, resulting in higher circulating concentrations of the active drug in the plasma.(6) Medications which commonly undergo extensive first-pass metabolism include alprazolam, amlodipine and dexamethasone. Conversely, if the medication is administered as a prodrug, reductions in therapeutic efficacy would be expected as reduced concentrations of the activated compound would be present in the plasma.(6)

5 Figure 2: Time concentration curves for orally administered paracetamol (Taken from Anderson (14) using data from Brown et al.(8) ) While differences in the processes of absorption may result in increased or reduced systemic bioavailability of drugs in neonates and infants when compared to older children and adults, it does not automatically follow that the doses of these agents will be modified according to only these factors. The recommended dose depends not only on changes in absorption, but also on changes in the distribution and elimination processes. For example, above it was identified that diazepam may have a lower bioavailability in infants under six months due to immature biliary function, leading to the conclusion that a higher dose may be needed in this age group to compensate. Infants under six months do have a higher mg/kg dose than children over twelve years, however the higher dose is not solely due to the change in the process of absorption. All children under twelve years have an increase in systemic clearance of diazepam, resulting in the use of an increased diazepam dose to achieve the same therapeutic effects. Absorption of drugs is generally discussed in terms of absorption following oral administration, however it is important to remember that absorption from other sites of administration can also be altered throughout childhood development. Rectal administration is not a reliable route of administration in young infants, as the administration of solid and semi-solid dosage forms will generally result in the dosage form being expelled

6 before the entire dose has been released because of the great number of high-amplitude, pulsatile contractions of the lower intestine experience by this patient group.(4, 6) If recommending a suppository for a younger patient, the pharmacist may suggest the parent or caregiver gently hold the buttocks for five to ten minutes if possible to reduce the pressure on the anal sphincter and minimise the risk of the rectal preparation being prematurely expelled. The rate and extent of absorption of drugs administered to the skin and intramuscularly relies on the blood supply to site of administration. Children generally have increased capillary density to these peripheral areas, and a larger surface area-to-volume ratio, compared to adults, and hence will usually have enhanced absorption from these administration sites.(4-6) Thus the general recommendation is to prescribe lower strength topical medications, like corticosteroids, to younger patients, with the emphasis being on localised application to the affected area only, to minimise the potential for extensive systemic absorption. Distribution Once a drug has reached the systemic circulation, it will distribute throughout the plasma and tissues. The extent of distribution of a drug is influenced by the ratio of total body water to total body mass of the patient, the concentration of plasma proteins, and physicochemical properties of the drug, such as the acid dissociation constant, the hydrophilicity (having an affinity for water; readily absorbing or dissolving in water ed.) or lipophilicity (fat-soluble ed.), and the protein binding affinity.(6) Total body water, as a proportion of total body weight, is highest in neonates approximately 75-80% of body weight compared with the adult value of about 60% which is reached by one year of age.(6) The higher percentage of total body water results in a higher volume of distribution (Vd) for hydrophilic drugs and a need for higher weight-based doses to achieve the same plasma concentrations as in adults.(4, 6) An example of an agent which is significantly affected by the changes in total body water is digoxin, where the dose on a mg/kg basis is significantly higher in infants than in young children, and higher in young children than in older children. The potential for an increased volume of distribution also has the potential to increase the half-life of hydrophilic drugs. Despite the relatively reduced proportions of body fat in infants, the changes in the volume of distribution of lipophilic drugs are not as readily apparent, and many show a similar Vd in infants and adults.(5) Changes in the Vd of drugs can also be observed for drugs which are moderately to highly protein bound when there are changes in the amount of protein in the plasma, when the affinity of the protein for the drug is altered, and when alternate substrates which have the capability to displace a drug from a protein binding site are present.(6) Serum albumin levels are reduced in neonates, and foetal albumin is still present, resulting in fewer binding sites and a reduced binding affinity.(6) Levels of other plasma proteins, such as alpha-1-acid glycoprotein and lipoproteins, are also lower in neonates, again resulting in a reduction in available binding sites.(6) Newborns are also known to have higher levels of bilirubin and free fatty acids in the plasma, resulting in an increased potential for drugs to be displaced from protein binding sites.(4, 6) Reductions in plasma protein binding, coupled with the increased potential for drugs to be displaced from protein binding sites, results in a higher proportion of free drug and it is the free drug that is the active moiety. The clinical significance of the increased proportion of free drug is variable and hard to predict. There is the potential for the increase in free drug to result in increased therapeutic, and adverse, effects. However, it is also likely that compensatory increases in volume of distribution and clearance may occur as more free drug is available to diffuse into the tissues or be eliminated from the body. Whether or not these compensatory measures are sufficient to return free concentrations of drug back to normal depend strongly on the elimination pathways

7 for the drug in question, and whether these pathways are mature or not, and the extent to which the drug is protein bound, as a more pronounced increase in free levels will be seen in drugs with higher degrees of protein binding. Ultimately, it is important to be aware that drugs which have a significant degree of protein binding are likely to exhibit an alteration in their pharmacokinetic profile in neonates and infants. Metabolism Hepatic metabolism is one of two major routes of elimination of drugs from the body and is comprised of both Phase I and Phase II metabolic processes. Phase I metabolism involves oxidation, reduction, hydrolysis and methylation reactions that serve to increase the polarity of a drug molecule, to aid in the compound being excreted more readily from the body. Phase II metabolism involves conjugation reactions that convert drugs to more water soluble compounds ready for excretion. Drugs may undergo either or both types of metabolism during their elimination. At birth, both Phase I and Phase II metabolic enzymes may be immature,(5) and each individual enzyme isoform develops and matures at a different rate.(4) Studies have consistently demonstrated an agedependent increase in plasma clearance of drugs which undergo hepatic metabolism in children under 10 years of age when compared with adults.(4) Phase I activity in particular is reduced in neonates, increases progressively during the first 6 months of life, exceeds adult rates by the first few years for some drugs, slows during adolescence, and usually attains adult rates by late puberty.(9) Half-lives of medications cleared by the CYP pathways are significantly longer than adult values in the very young and significantly shorter than adult values in infants and children over six months (Figure 3). Figure 3: Half-lives of medications cleared via Phase I metabolism (data of 18 substrates of CYP pathways - *p <0.05; **p < 0.01; ***p < 0.001; ****p < ) (Taken from Ginsberg et al. (9)) Many of the older anticonvulsant agents, such as phenytoin and diazepam, are predominantly cleared by Phase I metabolic pathways. For example, phenytoin is reported to have a maximum velocity of metabolism of 18.5 ± 7.5mg/kg/day in four to six year old children, compared to 11.9 ± 5.3mg/kg/day in the year old age group.(10) The difference in metabolic capacity between adults and children results in many drugs which are hepatically cleared, such as phenytoin and diazepam, requiring a higher dose (on a mg/kg basis) in children

8 between two years and puberty to obtain the same therapeutic plasma concentrations. For example, when used in status epilepticus, diazepam is dosed at mg/kg i.v. (up to a maximum of 10mg) in children under 12 years and dosed at a fixed dose of 10mg for children over 12 years. Children over 12 years will generally weight above 50kg, so will be dosed at a maximum of 0.2mg/kg. This lower dose corresponds to the lower metabolic function once puberty is reached. Excretion Renal excretion is the second major route of drug elimination from the body, and depends on plasma protein binding, renal blood flow, glomerular filtration rate (GFR) and tubular secretion. All of these factors are altered in the first two years of life. Although nephrogenesis is complete by 36 weeks of gestation, maturation of the kidneys continues throughout childhood.(6) Renal plasma flow is low at birth (12 ml/min) and reaches adult levels of 140 ml/min by one year of age.(11) While the GFR is approximately 2-4 ml per minute per 1.73 m 2 in neonates born at term, it may be as low as ml per minute per 1.73 m 2 in preterm neonates.(4) The GFR increases rapidly during the first two weeks of life and then rises steadily until adult values are reached at 8 to 12 months of age.(4) Similarly, tubular secretion is immature at birth and reaches adult capacity during the first year of life.(4) The potential for reduced plasma protein binding, and a subsequent increase in free drug and elimination rates, has been discussed above. Half-lives of drugs which are renally cleared are often significantly longer than adults in the neonatal period (Figure 4). These would be increased further in neonates born prematurely, subject to perinatal asphyxia, or with sepsis.(12) The clinical consequences of the differences in renal function is that many drugs which are primarily renally cleared, particularly antibiotics such as tobramycin, gentamycin and vancomycin, will require lower doses and less frequent dosing intervals when administered during the newborn period. Dosing medications in children Dosing of medications for children is usually based on the child s weight or body surface area. Doses and dosing intervals will differ to those used for adults due to the age-related variations in pharmacokinetics discussed above. It is not safe practice to give an adult dose to a child or to assume that the child dose will be proportional to the adult dose e.g. you cannot assume that the dose for a 14kg child will be one-fifth the dose recommended for a 70kg adult. Paediatric dosing guidelines may recommend a range of strategies to adjust doses for paediatric patients, including reduced doses, extended dosing intervals, and adjustments based on therapeutic response. Such guidelines should always be used to determine an appropriate starting dose for children less than twelve years of age. However, even within a population of similar age and weight, drug requirements may differ because of maturational differences in pharmacokinetic parameters. Thus, when practical, dose adjustments should be based on plasma drug concentration. Internationally, a range of paediatric prescribing guidelines, including Neofax (a Micromedex companion product) and the BNF for Children ( a British National Formulary companion product), have been available for many years. However, paediatric prescribing in Australia has long been troubled by a lack of approved drug information specifically relating to paediatric patients and an Australian guideline on paediatric prescribing, resulting in frequent off-label medication use.(13) Recently, the AMH has released its Children s Dosing Companion, a national guide for use in Australia to inform prescribing and administering medicines for young people which will help to address the historical gap in national prescribing guidelines. The Children's Dosing

9 Companion provides detailed dosing information for individual drugs, with dosages arranged by indications and/or age groupings from infants to 18 years, as well as other specific information relating to each drug s paediatric use. It also contains more general information on paediatric prescribing and managing drug use, including off-label use and other hard-to-find data. The use of this dosing companion, or a similar paediatricspecific pharmacopoeia, is essential when prescribing or evaluating medication use in children. Conclusion The differences between the pharmacokinetics of paediatric patients and the general adult population are significant and in many instances a number of factors need to be considered when dosing children that may affect therapeutic outcomes. Maintaining an awareness that children will generally process drugs differently to adults is imperative when working with this patient population. Because the differences are hard to predict, and the significance of the differences will vary depending on the individual drug and the age and health status of the child, the use of evidence-based paediatric prescribing guidelines is vital in ensuring safe and efficacious use of medicines in paediatric patients.

10 References 1. Freed GL, Sewell J, Spike N, Moran L, Brooks P. Changes in the demography of Australia and therefore general practice patient populations. Australian Family Physician. 2012;41(9): Australian Institute of Health and Welfare. Child health, development and wellbeing. Australian Government 2012 [cited 2013 September]; Available from: 3. World Health Organisation. Promoting safety of medicines for children. France: World Health Organisation, Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology- drug disposition, action, and therapy in infants and children. New England Journal of Medicine. 2003;349: Bartelink IH, Rademaker CMA, Schobben AFAM, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clinical Pharmacokinetics. 2006;45(11): Wagner J, Abdel-Rahman SM. Pediatric pharmacokinetics. Pediatrics in Review. 2013;34: Benedetti MS, Baltes EL. Drug metabolism and disposition in children. Fundamental & Clinical Pharmacology. 2003;17: Brown RD, Wilson JT, Kearns GL, Eichler VF, Johnson VA, Bertrand KM. Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. Journal of clinical pharmacology. 1992;32(3): Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, et al. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicological Sciences. 2002;66(2): Suzuki Y, Mimaki t, Cox S, Koepke J, Hayes J, Walson PD. Phenytoin age-dose concentration relationship in children. Therapeutic Drug Monitoring. 1994;16: Berlin CM. Principles of drug treatment in children. New Jersey, USA: Merck Sharp & Dohme Corporation; 2009 [cited 2013 September]; Available from: Ligi I, Boubred F, Grandvuillemin I, Simeoni U. The neonatal kidney: implications for drug metabolism and elimination. Current drug metabolism. 2012;14(2): Ballard CDJ, Peterson GM, Thompson AJ, Beggs SA. Off-label use of medicines in paediatric inpatients at an Australian teaching hospital. Journal of Paediatrics and Child Health. 2013;49: Anderson BJ. What we don't know about paracetamol in children. Pediatric Anaesthesia. 1998;8:

11 MCQs Questions based on the above article: Select ONE alternative that best represents the correct answer to each of the following multiple choice questions 1. Which of the following is NOT a change to absorption likely to be seen in neonates? a. increased gastric ph resulting in an increased bioavailability of acid labile drugs b. decreased bile acid salt formation resulting in a reduced bioavailability of lipid soluble drugs c. slowed gastric emptying resulting in a reduced rate of absorption d. reduced expression of CYP enzymes in the intestinal lumen resulting in an improved bioavailability of drugs which would commonly be subject to high first pass metabolism e. elevated gastric ph resulting in improved bioavailability of weakly acidic drugs 2. Which of the following describes a way in which distribution of drugs in children differs from that in adults? a. children have a higher proportion of body fat, increasing the volume of distribution of lipid soluble drugs b. levels of albumin are generally increased, resulting in more protein binding and a smaller volume of distribution c. concentrations of endogenous compounds, such as bilirubin, are lower enabling more protein binding to occur d. children have a higher proportion of total body water, increasing the volume of distribution of hydrophilic drugs e. foetal albumin provides more binding sites and a higher binding affinity than mature albumin 3. With regard to the metabolic clearance of drugs, which of the following statements is TRUE? a. Phase I metabolism converts drug molecules to more water soluble compounds through conjugation reactions b. metabolic pathways are mature by birth in full term neonates c. Phase I activity exceeds adult rates for a large proportion of childhood d. children require lower doses for many drugs (on a mg/kg basis) than adults e. drugs either undergo Phase I or Phase II metabolism, never both 4. The GFR of full term neonates is: a mL/min b. 2 4mL/min c mL/min d. 120mL/min e. 140mL/min 5. When choosing a dose for a medication in children, the dose will NOT be: a. based on weight or surface area b. directly proportional to adult doses c. different between children due to maturation differences d. best guided by paediatric dosing guidelines e. ideally adjusted based on plasma drug concentrations