20 - Pain - Assessment
Editors: Goldman, Ann; Hain, Richard; Liben, Stephen
Title: Oxford Textbook of Palliative Care for Children, 1st Edition
Copyright 2006 Oxford University Press, 2006 (Chapter 34: Danai Papadatou)
> Table of Contents > Section 3 - Symptom care > 18 - Using medications
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18
Using medications
Nigel Ballantine
Nicki Fitzmaurice
The term therapeutic orphans was coined by Shirkey in 1968, when referring to the lack of a sound scientific base for the delivery of drug treatment to children and neonates [1]. More than three decades later, whilst our understanding of the maturation of physiological processes has undoubtedly grown, enabling drug treatment to be delivered to children from a more informed position, children, and particularly, certain groups of children, remain therapeutic orphans. This is particularly true of those receiving palliative care, where the complexities of the interaction between maturing physiological function, underlying disease, terminal illness, and ethical considerations result in a paucity of research and data. These difficulties are addressed in the following sections through an examination of the maturation of pharmacokinetic and pharmacodynamic functions, the effect of disease using the example of cystic fibrosis, and the effect of acute illness as a proxy for some of the changes that are likely to occur during palliative care.
Pharmacokinetics
Variability in drug response may be due to differences in:
patient age
organ maturation
pharmacokinetics
pharmacodynamics
efficacy
toxicity
concomitant disease and drugs
race or genetic status
method of drug administration
dosage forms
stability and compatibility
compliance with therapy [2].
Pharmacokinetics uses mathematical models to describe the ways in which the body handles administered drug, through the processes of absorption, distribution, metabolism, and excretion. Age-related changes in drug distribution and handling are not well understood, and yet, are crucial to appropriate dosing of children. In palliative care, the complexities of such changes in the well child must be taken into account, as also changes in drug handling associated with the patient's underlying disease, and also any changes specific to the palliative phase. This section aims to provide an overview, but data is often hard to find. Changes occurring within a particular age range may proceed at varying rates in individual subjects, and developing physiological functions vary in their rate of change over time [3]. Marked variations in the rate of change are seen around landmarks such as adolescence and transitions between growth phases. But younger age does not necessarily mean that drug handling mechanisms are less well-developed. Amongst children aged between 3 months to 17 years who were receiving chlorpromazine, Furlanut et al (1990) found a high correlation between age and half-life, with the mean half-life amongst the group shorter than that reported for adults [4]. The association between age and maturation of drug handling is dependent on interaction between anatomic, physiologic and chemical factors that are, in turn, age-dependent.
Research into drug handling mechanisms in children has largely focussed on the functional development that follows birth, and these have been reviewed in published papers and in textbooks [5, 6].
Factors affecting GI absorption
The gastric mucosa is able to secrete gastric acid within minutes of birth at full term, with output increasing over several hours, but gastric pH may initially be alkaline, due to the presence of amniotic fluid. Subsequently, little is known about the secretion of gastric acid; such studies that have been carried out are difficult to compare, due to methodological differences.
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Evidence suggests that in full-term neonates, basal and stimulated gastric acid secretions, expressed as mEq/kg/h, are similar in the first few days of life. A trough in both occurs at around 1 month, but by 1 year, stimulated acid secretion exceeds basal secretion, and by 2 years of age, acid output (kg -1) is similar to that of adults [7], although essentially adult levels of function may be achieved considerably earlier [8].
Gastric emptying time (GET) is significantly influenced by gestational and postnatal age [8]. It is delayed in the first 24 hours of life for both full-term and premature neonates. Thereafter, a healthy neonate has a GET similar to an adult's (25 87 min vs 22 53 min), although significant differences have been reported, with others reporting adult GET by 6 8 months [7, 8].
Intestinal transit time is less well studied than GET. Transit times of 3 to 13 hours have been reported in full-term neonates three to five days old. Longer transit times are found in breast-fed babies 45 days old, compared to those of the same age fed on formula milks. In the neonate and young infant, factors such as immaturity of the intestinal mucosa and biliary function, high intestinal -glucuronidase activity, and variable intestinal colonisation may all influence drug absorption [7].
Amylase and other pancreatic enzymes show low activity in the duodenum up to the age of 4 months. -amylase cannot be detected in the duodenum during the first month of life in premature neonates born at 32 34 weeks, and remains at low levels throughout the first year of life [8]. Lipase activity is present before birth, and increases 20-fold in the first 8 months of life [8]. Similarly, trypsin secretion, stimulated by pancreozymin and secretin, develops through the first year of life. Drugs requiring hydrolysis by pancreatic enzymes are unreliably absorbed in the first few months of life.
The bile acid pool in neonates is 50% of adult values in newborns, and 33 50% in premature neonates. The reduced pool is due to ineffective ileal reabsorption and increased jejunal permeability. The absorption of lipid soluble drugs and those that undergo enterohepatic re-circulation may be adversely affected.
Such differences suggest explanations for different drug bio-availability in neonates, and young children compared to adults, but many studies that seek to investigate these differences fail to consider all possible variables. In neonates, higher plasma concentrations and area under the concentration-time curve for several penicillins, compared with those found in older children and adults, are commonly explained by enhanced absorption due to achlorhydria. But it has been suggested that these differences may be due to decreased renal function.
Mucosal enterocytes in the small intestine possess cytochrome P450 drug metabolism enzymes [9]. Grapefruit juice markedly inhibits cytochrome enzymes in the intestinal mucosa, and may increase the absorption of drugs such as midazolam, ciclosporin and terfenadine by up to 50%, if taken in sufficient quantities an hour before drug ingestion. The flavenoids naringenin and quercetin are thought to be involved, and are also present in health food supplements available over-the-counter.
Drug absorption across other mucosal membranes
Percutaneous drug absorption depends on the effect of maturational changes in the skin, including vascularisation and development of exocrine and apocrine glands and the corneal strata. Little is known of how these changes affect percutaneous drug absorption, but the higher ratio of body surface area to body weight in the neonate, compared to an adult, is important. Drug absorption across the same area of skin will result in higher absorption, corrected for body weight, in the neonate. Such differences are responsible for the developmental problems associated with the use of hexachlorophene-containing products in neonates. The poorly developed epidermal barrier in pre-term infants has been exploited through the use of theophylline presented as a topical gel. However, absorption declined steadily after the first 24 h of life.
In the newborn and infant, the rectal route of drug administration can also be effectively utilized, using suitably formulated drug preparations [7].
Drug Distribution
Factors affecting drug distribution include vascular perfusion, body composition, tissue binding, and binding to plasma protein. All are subject to maturational changes.
Whereas drug administered parenterally is distributed directly to the heart and lungs, drug administered orally is delivered primarily to the liver. First-pass metabolism, the metabolism which occurs during the drug's, transit through the liver, following absorption, and before it reaches the systemic circulation, may result in very little parent drug reaching its site of action, although for prodrugs it may be essential to producing physiologically active drug.
Vascular perfusion may have a significant effect on drug distribution. Persistent fetal circulation produces a shift in blood flow from the lungs to other organs and tissues. In such cases tolazoline may produce peripheral rather than pulmonary vasodilation when used to treat pulmonary hypertension.
Body composition differs considerably between the neonate and adult. Total body water, as a percentage of body weight, falls from 87% in the pre-term neonate, to 77% at full
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Table 18.1 Effect of age on organ weight as percentage of body weight [5] | ||||||||||||||||||||||||||||||||||||
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term, 73% at 3 months of age, 59% at 1 year and 55% in adulthood. Extracellular water falls from 45% of total body weight at full term to 33% at 3 months, 28% at 1 year and 20% in the adult. Adipose tissue changes both qualitatively and quantitatively through gestation and after birth. Quantity increases rapidly in the first year of life, and neonatal adipose tissue contains 57% water, compared to 26.3% in the adult [7]. At puberty, gender differences in percentage of adipose tissue become apparent. Males lose 50% of their body fat between the ages of 10 and 20 years, whilst females lose only 3% [7].
Tissue binding is predominantly determined by the physicochemical properties of the drug substance, as also by variables identified previously. In addition, the mass of organ tissue varies considerably with age (see Table 18.1).
Blood provides many sites for drug binding which may show age-related changes. Neonatal erythrocytes have 2.5 times more binding sites for digoxin than adults, with the erythrocyte: serum ratio for neonates stabilised on digoxin being 3.6, compared to 1.3 in adults. Such differences help to explain differences in neonatal and adult dosing requirements.
Plasma protein binding
Changes in plasma protein binding are due to changes in both the amount and quality of plasma protein, as well as the affinity of drug for binding sites. Albumin is the major drug binding protein in plasma for acidic drugs and other molecules, including fatty acids and bilirubin. Basic drugs favour 1-acid glycoprotein and lipoproteins over albumin, whilst other drugs bind to transcortin, fibrinogen and thyroid-binding globulin. Serum levels of albumin in neonates are similar to those in adults, but 1-acid glycoprotein levels are lower. Other age-related differences in plasma protein include the persistence of fetal serum proteins, hypoproteinaemia and the presence of ligands, including endogenous plasma globulins and bilirubin, which compete for binding sites. Altered bound: free drug ratios in neonates may result with consequences for the pharmacologic profile of a drug. Many drugs are less bound to serum protein in neonates as compared to adults, although the opposite is true of dexamethasone, which is more highly bound to neonatal than maternal protein. Phenytoin, which is 94 98% bound to albumin in adults, but only 80 85% in neonates, illustrates this point [7]. Since bound and free drugs are in equilibrium, the total blood drug level for a given concentration of free (active) drug will be lower in the neonate than the adult. The therapeutic range, which is based on drug concentration in whole blood, will be lower in consequence. It is essential, when monitoring drug levels, to understand whether it is free or total drug concentrations that are being measured.
Many pathological conditions, including acidosis, malnutrition (hypoproteinaemia), hepatic and renal disease, cystic fibrosis, burns and trauma, and malignancy and surgery, have been shown to alter the protein binding of drugs. Typically, these increase the percentage of unbound drug, leading to increased pharmacological responses and toxicity. Following displacement, a greater amount of unbound drug is available for clearance, however, which explains why altered binding in disease, demonstrated in vitro, is not necessarily clinically significant.
Changes in drug-protein binding chiefly affect drugs with capacity-limited extraction and high protein binding (> 85%). The best-known example of toxicity attributed to altered protein binding is probably the kernicterus, which may occur when highly protein-bound drugs such as sulphonamides are administered to neonates [10]. This explanation has been, disputed, however, since the affinity of bilirubin for protein-binding sites is greater than that of drugs, and the toxicity observed may be due to other mechanisms.
Age-related changes tend to increase the volume of distribution of water-soluble drugs, and decrease that of lipid-soluble drugs. Increased volume of distribution results in a greater amount of drug in the body, for a given serum concentration. Many age-related differences in drug distribution are relevant only in the first year of life. Thereafter, distribution is similar to that in adults.
Drug metabolism
Many organs in the body, including the blood, lung, GI tract, liver, and kidney are capable of metabolising drugs. Different metabolic pathways develop at different rates, both within and between individuals, and drug exposure in utero may induce
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such pathways. Such factors make prediction of the extent and efficiency of bio-transformation processes based on post-natal age extremely difficult. Normalization of volume of distribution and clearance to body weight, ideal or lean body weight, or body surface area is commonly carried out to correct for differences in parameters that are solely related to body size [11]. Which of these is most appropriate for individual drugs may depend on the particular pathways of bio-transformation and elimination.
Phase 1 reactions are principally non-synthetic, and are directed at detoxifying the drug molecule, although drug metabolites may be therapeutically active or toxic. The mixed function oxidase (MFO) system, which includes cytochrome (CYP) P 450, cytochrome b5 and NADPH cytochrome c reductase, is central to drug metabolism, and many factors control the rate of bio-transformation. These include the concentration of the metabolic enzyme, the proportion of the various forms, rates of reaction, and the affinity for the drug substrate. Furthermore, the presence of competing substrates, both exogenous and endogenous, affects the rate of bio-transformation.
The major components of the MFO system are present in preparations of human microsomes from both fetal and full-term samples. Cytochrome P 450 activity in the fetus and full-term neonate is between 50% and 75% of adult values. NADPH cytochrome c reductase activity is lower in the premature, compared to the full-term, neonate, and both are significantly lower than an adult. With both en zymes, there appears to be a relationship between activity and gestational and post-natal age.
The development of drug metabolising enzyme activity is well illustrated by the example of theophylline, a substrate for CYP1A2. In term infants at 6 12 weeks of age, the half-life is 8 18 h [7]. A linear relationship between age and half-life follows, with the latter falling to 3 4 h by 48 weeks of age. Adult levels of function of this iso-enzyme are reached by 3 months of postnatal age. Similarly, studies of CYP3A4, using carbamazepine and midazolam as substrates, demonstrate low levels of activity in the foetus, increasing rapidly in postnatal life to adult levels by 3 12 months of age. Development continues until adolescence, when activity declines to adult levels [7]. Substrates for this iso-enzyme include nifedipine, lidocaine, ciclosporin and tacrolimus, illustrating its importance to paediatric practice.
Studies of drugs commonly administered to infants, including diazepam, caffeine, phenobarbital and phenytoin, demonstrate a low capacity for oxidative transformation in full-term infants, and almost none in pre-term neonates. The biological half-life of drugs metabolised by the cytochrome P 450-dependent mono-oxygenase system, including phenytoin and amobarbital, is generally longer in infants, compared to adults. The metabolism of phenytoin, a substrate for CYP2C9, indicates that, like ibuprofen, this iso-enzyme is more active in young children than adolescents and adults. Increased oxidative metabolism in the liver in patients with head injuries explains the higher dose requirements for lorazepam and phenytoin [2].
Studies in older children demonstrate marked inter-subject variation. Metabolic clearance in this age group is considered to be greater than that in adults, as demonstrated by the elimination of theophylline (CYP1A2), phenytoin (CYP2C9), carbamazepine (CYP3A4), quinidine and procainamide. This may be due in part to a greater liver weight, relative to body weight, in newborns and children, compared to adults [3]. When normalised for body weight or surface area, however, such differences were not seen with lorazepam, antipyrine and indocyanine green, respectively model substrates for glucuronidation, MFO bio-transformation and flow dependent metabolism [7]. Growth hormone activity at different stages of development may influence specific drug metabolising enzymes.
The cytochrome P450 system is subject to polymorphism, such that 3 variants of CYP2C9 associated with point mutations are recognised. The clearance of phenytoin and ibuprofen is influenced by the CYP2C9 genotype. Similarly, extensive metabolisers (93% of white and black patients) of tramodol, a substrate for CYP2D6, show significantly greater analgesic effects and frequency of adverse events, due to the increased formation of O-Desmethyl-tramodol, a metabolite with potency 6 times greater than the parent compound [7]. Some iso-enzymes of the cytochrome P450 system are male-specific, or regulated by male-specific factors, such as steroid hormones [12]. Establishment of the menstrual cycle may also be an important source of hormone related changes in hepatic metabolism. Menstrual-cycle-related changes in methaqualone metabolism result in clearance mid-cycle, twice that on day 1. C-oxidation (a cytochrome P450 function) was also greater on day 15, compared to day 1 [12]. Sexual maturation has also been shown to influence the activity of the CYP1A2 and CYP2C9 iso-enzymes, but not that of CYP3A4 [7]. Oral contraceptive use by post-pubertal women represents a special case of gender difference in drug handling. The mid-cycle increase in methaqualone metabolism is abolished by concurrent oral contraceptives, which inhibit the metabolism of a number of drugs subject to phase I oxidation, including aminopyrine, some benzodiazepines, caffeine and imipramine. This is believed to be due to a reduction of cytochrome P450 content, caused by the oestrogen component. In contrast, increased clearance of drugs eliminated by glucuronidation has been shown for paracetamol, clofibrate, diflunisal, lorazepam, oxazepam and temazepam.
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Phase 2 reactions consist principally of conjugation of drug and/or metabolites with endogenous molecules to produce a compound with greater water solubility than the parent. Hepatic microsomal enzymes also catalyse these reactions, with the most common being glucuronidation, sulfation, acetylation and amino acid conjugation.
Thiopurine methyltransferase activity is 50% higher in newborn infants than in adults [7]. Women show 70% higher peak plasma concentrations of propranolol, compared to men, due to reduced side-chain oxidation and glucuronidation reactions, and subsequently clearance [12]. The case of methylprednisolone illustrates the complexity of competing processes. Women show greater sensitivity to methylprednisolone-induced cortisol suppression than men. But they also metabolise methylprednisolone more rapidly, possibly due to greater activity of CYP3A-mediated hydroxylation, resulting in similar net cortisol suppression in both sexes.
Sulfation is well developed in term newborns [13], and is an essential alternative conjugation pathway for acetaminophen in the neonate, since glucuronidation in this age group is less well-developed. Evidence exists that sulfation capacity decreases with age [13], with formation rate constants in patients aged 7 to 10 years exceeding adult values. Adolescent and adult handling of paracetamol by sulfation are not considered to differ. Premature neonates acetylate drugs such as sulphonamides more slowly than full-term neonates, while both do so more slowly than adults. In the case of this reaction, genetically determined fast or slow acetylator status may also be important, as it is in adults, although it is less well characterised in children. Amino acid conjugation is present at birth, and reaches adult values at around 6 months of age.
It is known that the ability to acetylate a number of drugs including isoniazid, sulfonamide antibiotics, hydralazine and procainamide shows a genetically determined bimodal distribution. Different ethnic groups demonstrate different proportions of fast acetylators; for example, 88% of Japanese-Americans compared to 56% of Caucasian Americans. Some evidence suggests that the proportion of fast acetylators increases with age [13]. Keruegis et al. showed that 62.5% of adolescents less than 15 years old demonstrated the fast acetylator phenotype, compared to 38% in older subjects, although this difference was not statistically significant. Singh found weight-adjusted clearance and elimination rate constants in children aged 7 12 to be twice those reported in adult studies, although the study could not exclude other explanations for the observed difference. The half-life of sulfamethoxazole correlates with age, showing a two-fold difference between children <10 years old and adults, when corrected for differences in volume of distribution [13].
Similarly, debrisoquine hydroxylase deficiency may be important both because of its relative rarity in Caucasians (5%), and because more than 30 drugs are known substrates for the enzyme [11].
Glucuronidation occurs mainly in the liver and kidney, and occurs through the donation of glucuronide groups by uridine diphosphate-glucuronic acid in reactions catalysed by the family of microsomal uridine diphosphate-glucuronyl transferases (UDPGT's). These reactions are important to the metabolism of a number of drugs administered to children, including morphine, paracetamol, zidovudine, lorazepam, naloxone, diclofenac and chloramphenicol, as well as endogenous substrates including steroids and bilirubin [7]. The inability of some neonates to conjugate bilirubin results in high levels of unconjugated bilirubin that can diffuse across the blood-brain barrier to cause kernicterus. The grey-baby syndrome caused by chloramphenicol is also due to decreased capacity for glucuronidation, as well as increased bio-availability [2]. Glucuronidation formation reaches adult values between 2 months and 3 years of age [7].
Evidence existing shows for differences in glucuronidation between older children and adults. Crom et al. reported a trend towards increased clearance and shorter half-lives for lorazepam in three subject groups: less than 13 year old, 13 18 years olds and adults [13]. Differences between the patient groups (for example, the adults were healthy subjects, whilst the children had acute lymphoblastic leukaemia in remission, suggesting the possibility that the changes were due to differences in body composition) make interpretation of the data difficult, however. Similarly, evidence for increased clearance and shorter half-life for lorazepam in young women taking an oral contraceptive is contradictory [13].
Zidovudine is believed to be metabolised by a UDPGT, and some evidence exists for a correlation between age and weight-adjusted clearance [13]. Whilst no differences in apparent clearance, apparent volume of distribution or half-life were seen during the menstrual cycle, the overall half-life in post-pubertal women is 3 4 h longer than in studies which have used predominantly male subjects [13].
In general, the plasma kinetics of morphine in children over 1 year old are reported as being similar to those found in adults [14]. Differences are seen in plasma clearance between premature and full-term infants, whilst children and adolescents show similar or higher clearance values compared with adults (13 15). Clearance in infants less than 1 month old is only 25% of that of 6-month-old infants (half-life of 7.3 h compared to 2.3 h).
Ethnicity may influence morphine pharmacokinetics. It has been reported [16] that despite higher levels of morphine-6-glucuronide, Caucasians are less susceptible to morphine-induced
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depression of the ventilatory response to carbon dioxide re-breathing than native (South American) Indians or Latinos.
Similarly, paracetamol half-life shows no difference between young children, 12 year-olds and adults, although glucuronidation rates increase until they level off around the age of 12 years.
Nevertheless, there is a trend to higher oral clearance of paracetamol during the follicular and luteal phases of the menstrual cycle, compared to clearance in the menstrual phase and in males [13].
In general, bio-transformation of most drugs is decreased in the neonates, increasing from the ages of 1 5 years and then declining to adult values following puberty. An exception is amphotericin B, where the clearance is markedly decreased in patients between the ages of 1 and 10 years [2].
A further complication of many studies of drug metabolism in children is the co-administration of enzyme inducing drugs. These may induce the metabolism of other drugs or themselves. The mechanism is believed to be an increase in synthesis of enzyme protein. In the non-induced infant in the first 2 weeks of life, drug bio-transformation is reduced. For most drugs, this is not a major problem, since deficiency of the primary metabolic pathways is often compensated for by the presence of alternatives pathways, as with acetaminophen and salicylates. Problems may occur, as with chloramphenicol, when alternative pathways do not exist unless there is strict observance of dosage, and serum level monitoring is performed.
Such interactions can have significant effects. The area under the plasma concentration time curve (AUC) for midazolam is reduced by 96% when rifampin is administered concurrently, making sedation using midazolam difficult, if not impossible [9].
There remains no proxy of liver metabolic function, such as serum creatinine provides in respect of renal function. Studies in older children have demonstrated a correlation between liver volume (standardised by unit of body weight) and age, whilst in adults, a correlation has been shown between antipyrine clearance and liver volume. Such data does not as yet, however, permit this approach to predict drug metabolic function in general.
Renal elimination
Whilst the liver is the primary organ of drug metabolism, the kidney is the major route of elimination of water-soluble drugs and metabolites. The three mechanisms involved are glomerular filtration, tubular secretion, and tubular reabsorption. Renal blood flow is an important determinant of glomerular filtration, and therefore, drug elimination.
The neonatal kidney is inefficient at drug elimination, which results in prolonged elimination half-lives for drugs such as aminoglycosides, digoxin and furosemide. Maturation of the processes of filtration, secretion and reabsorption occurs at different rates, and may be influenced by a number of factors, including maternal drug use.
The premature neonate is born with a reduced number of functioning nephrons, compared to its full-term counterpart [7]. The latter's kidneys, whilst having a similar number of nephrons to an adult, has greatly reduced renal function, compared to older children and adults, even when standardised for body weight, body surface area, extracellular fluid volume and kidney weight. Functional development of the kidney during the neonatal period, particularly between the 34th and 36th weeks of gestation, is the result of a balance between filtration and secretory mechanisms on the one hand, and reabsorption on the other. Glomerular filtration rates increase significantly in the first 2 weeks of life, and do so more quickly than tubular function. This imbalance persists until 6 10 months of age [7]. Clearance of drugs may be greater in infants than in older children, due to slower development of reabsorption processes. The underlying disease state may also be significant, with hypoxia causing impairment of tubular function in the neonate and changes to normal kidney development. Thereafter, renal function remains essentially constant through to adulthood, although there is substantial variability in renal function in the general population [11].
The renal handling of digoxin illustrates the differential maturation of the processes of renal function. In full term neonates, digoxin clearance exceeds creatinine clearance indicating the present of mechanisms other than filtration: a phenomenon not seen in other age groups [10]. The increase in digoxin clearance in the first few months of life indicates the initial immaturity of these mechanisms. Thus mean renal clearance of digoxin at 1 week of age is 32.9 7.4 ml/min-1 .1.73 m-2, increasing to 88.9 23.8 ml min-1. 1.73 m-2 and 144.4 38.4 ml min-1. 1.73 m-2 at 3 months and 1.5 years respectively. Premature neonates demonstrate longer half-lives than their full-term counterparts, with mean renal clearance of 10.4 ml min-1. 1.73 m-2 being determined from seven premature neonates studied. The half-life mirrors clearance, falling from 20 to 76 h in full-term neonates less than 2 months of age to 12 42 h at 16 months of age.
Passive filtration of drug is determined by the unbound fraction, renal blood flow and the area and nature of the glomerular membrane, and each of these is influenced by maturational changes. In the full term neonate, glomerular filtration is around 40% of the adult, reaching a maximal value at around 3 years or earlier [3], when corrected for body size. Glomerular filtration rate (GFR) is lower in premature
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neonates than in their full-term counterparts. Much has been published on the dosing of aminoglycoside antibiotics, including amikacin, gentamicin, and tobramycin, in neonates, since these drugs are primarily excreted by glomerular filtration. Most dosing recommendations suggest a starting dose, and subsequent serum level monitoring as a basis for dosing, since GFR and aminoglycoside clearance is reduced during the first week of life and subsequent maturation depends on birth weight, concurrent disease, and drug therapy.
Tubular function requires both energy and carrier molecules, and consists of separate systems for organic acids and bases. The capacity of the kidney to secrete weak acids, such as penicillins and cefalosporins, is markedly reduced in the neonate, although there is evidence that the secretory mechanism may be stimulated by repeated exposure to drug.
Tubular reabsorption of drug may involve both passive diffusion and active transport. The former is more common and depends on the degree of ionisation of the substance, urinary pH, urine flow and tubular surface area. Passive reabsorption in neonates is decreased, with the ability to reabsorb glucose, sodium and phosphate increasing with age. With their different sleep pattern, decrease in urinary pH during sleep does not occur in neonates as it does in adults. The elimination of acidic drugs is enhanced by the more alkaline environment, in which more drug is ionized, and therefore, less reabsorbed.
Renal function also matures due to changes in renal blood flow (arising from increased cardiac output or decrease in vascular resistance, or both) and redistribution of blood flow between the intrarenal regions and the cortex.
Gender differences can be found in respect of renal function, as with liver function. The renal clearance of amantadine has been reported as 14 L/h1 in men and 9 L/h1 in women. Concurrent administration of quinine or quinidine reduces the renal clearance of amantadine in men, but not in women [12].
Circadian rhythms
Drug absorption, distribution, metabolism, and renal elimination display significant daily variations in common with nearly all functions of the body [17]. Asthma attacks occur most commonly around 4 AM. Children show the same pattern of highest blood pressure and heart rate during the daytime, followed by a nightly drop and an early morning rise, as do normotensive adults and those with primary hyper-tension. Cardiovascular drugs, anti-asthmatics, anti-cancer drugs, psychotropics, analgesics, local anaesthetics and antibiotics demonstrate pharmacokinetics which are not constant throughout the day. Circadian rhythms undergo maturation with development, and the scheduling of doses has the potential to alter drug response. It is now inappropriate to consider that pharmacokinetic parameters are independent of the time of day.
Theophylline was one of the first drugs for which daily variations in pharmacokinetics were identified. Peak drug concentrations are lower, and time to peak drug concentration longer, after dosing in the evening, compared to the morning, possibly due to slower absorption. In consequence, theophylline should be given as a single evening dose, or the evening dose should be weighted, compared with doses given earlier in the day. The same picture is seen with terbutaline. In contrast, anticholinergics and inhaled beclomethasone (beclometasone) have a more pronounced effect at night. These results suggest that a plasma level: time relationship which is a flat line may not be the most appropriate to match drug exposure to clinical symptoms. Similarly, the assumption that a continuous infusion of drug produces a constant serum concentration is no longer valid. Continuous infusion of ranitidine produces greater increases in gastric pH during the daytime than at night. The proton pump inhibitors omeprazole and lansoprazole are also more effective if administered in the morning, although, at least for lansoprazole, this may be due to decreased absorption if dosed in the evening. The higher peak plasma levels and shorter time to peak levels for propranolol and calcium channel blockers when dosed in the morning are assumed to be due to faster gastric emptying time and higher gastro-intestinal perfusion at this time of day, compared to the evening.
Elimination, as well as absorption, is influenced by these rhythms. In children less than 1 year old, sulfisomidine elimination rate was 20% lower at night than during the day, indicating variation in non-ionic tubular reabsorption.
In children acute lymphoblastic leukaemia with (ALL), the elimination half-life of 6 mercaptopurine is significantly longer in the evening, compared to the morning, (7.1 v 2.9 h) during maintenance therapy. This difference is such that in 188 children studied, evening dosing, compared to morning dosing, resulted in a significant increase in disease-free survival.
Pharmacodynamics
Pharmacodynamics describes the biochemical and physiological effects of drugs, providing a correlation between action and chemical structure. Whilst the amount of information available on drug pharmacokinetics in children is relatively small, the situation is even less clear in respect to pharmacodynamics. This is partly due to the relatively recent appreciation of the importance of these phenomena, and partly due to the difficulty in separating the influence of pharmacokinetic variables from pharmacodynamic ones, unless the study is specifically designed to do so.
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Some pharmacodynamic issues have been addressed in previous discussions, including differences in drug response apparently influenced by gender. Gender differences in response to a number of drugs have been reported, including general and local anaesthetics, salicylates, hypoglycaemics, imipramine, diazepam and phenothiazines [12]. Post pubertal women may respond differently to anti-psychotic drugs, possibly due to higher hormonal concentrations or hormonal effects on receptors. Responses and adverse reactions to anti-depressants may vary by gender [12]. Differences in insulin sensitivity have also been seen between male and female adolescents with insulin-dependent diabetes mellitus. The female subjects demonstrated reduced sensitivity to insulin compared to the males, an effect postulated to result from differences in levels of growth hormone between the sexes during the early phase of hypoglycaemia.
The maximum tolerated dose (MTD) for a number of anti-cancer drugs has been shown to be greater in children than in adults [11]. The MTD for etoposide in children is 1.2 times that for adults; for amsacrine and daunorubicin, 1.25 times, and for doxorubicin and teniposide, 1.33 times. These differences may be due to pharmacokinetic differences, such as more rapid clearance, or pharmacodynamic differences in, for example, end organ sensitivity. Children are known to clear methotrexate more quickly than adults, although significant variability exists at all ages.
The IC50 for IL 2 expression in peripheral blood monocytes exposed in vitro to ciclosporin has been shown in infants less than 12 months of age to be 50% of the value found in older children. This difference appears to be based on a true difference in drug: receptor interaction.
Cystic fibrosis
It is well established that in children and adults, underlying disease may affect the distribution of drugs, although this is much more widely studied in adults. In children, the disease most investigated in terms of altered drug distribution is cystic fibrosis (CF) [11]. CF may be the only disease in which certain parameters of drug metabolism are increased [9]. In 1975, Jusko et al. first demonstrated increased creatinine clearance and atypical drug distribution of dicloxacillin in patients with CF [18]. Since then, much work has elucidated the mechanisms by which drug handling is altered in CF. 85 90% of patients with CF have symptoms of GI dysfunction, including hypersecretion of gastric acid and duodenal aspirates which are small in volume, viscous, and containing low concentrations of bicarbonate and pancreatic enzymes [8]. In consequence, a number of drugs, including cloxacillin, ciprofloxacin, clindamycin and cefalexin have significantly delayed absorption in patients with CF. The lower peak plasma/serum levels of cefalexin, dicloxacillin, epicillin and theophylline may in part be a consequence of impaired absorption, but may also result from increased volume of distribution and/or drug elimination.
Steatorrhoea in CF has been associated with malabsorption of fat-soluble vitamins, with clinical features of Vitamin A deficiency being seen even when pancreatic enzyme supplements are given. Vitamin K deficiency tends to occur in older patients, and correlates with the severity of liver and pulmonary disease, whilst deficiency of Vitamins A and D is common unless supplemented. Absorption of Vitamin B12 is impaired due to lack of a pancreatic factor and gastric hyperacidity.
Hypoalbuminaemia is common in patients with CF. It is most commonly due to increased plasma volume, secondary to pulmonary hypertension and cor pulmonale, but may also occur in infancy. As pulmonary disease progresses, serum immunoglobulins A and G concentrations may rise, and this hypergammaglobulinaemia may be important for the protein binding of basic drugs such as propranolol, methadone, tri-cyclic antidepressants and some local anaesthetics, which may counter-balance increased elimination. Only theophylline has been shown to have significantly decreased plasma protein binding, compared with controls.
It is proposed that the clearance of drugs should be normalised to lean body mass, in order to account for the significant differences in volume of distribution found for amikacin and ceftazidime. But this approach has been criticised for the difficulty it presents in comparing data from emaciated patients, in whom total body weight equals lean body mass, with that from better-nourished counterparts.
Typically the mean weight of the kidney in CF is 150% of that expected, and glomerulopathy has been demonstrated in patients as young as 4 months. Increases of 13.4% in glomerular filtration rate measured by insulin clearance have been demonstrated in patients with CF, with decreased tubular reabsorptive capacity for sodium. Other studies are contradictory, and comparisons are complicated by the different methodologies used. The expansion of plasma volume of 30 45% in patients with moderately severe CF may be another confounding factor.
In CF, increases in night time urine flow rate of 9.4 65.3% and 77% compared to controls have been demonstrated, consistent with an elevation of the filtration fraction. Dilution and a reduced time available for tubular reabsorption, resulting from increased urine volume and flow rate, may account for the 200% increase in the clearance of dicloxacillin in CF patients. The renal excretion of gentamicin and theophylline are also reported to be dependent on urine flow, and the increased elimination of trace elements may also be due to this effect.
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Mechanisms that may account for increased non-renal clearance of drugs include elimination in bile and bronchial secretions. The elimination of lipid-soluble drugs such as cloxacillin and furosemide in bile is increased in patients with CF, and, in the case of furosemide, is accompanied by a fall in urinary excretion.
Tobramycin has been found in markedly higher levels than normal in the bronchial secretions of CF patients. Correlation between clearance and disease severity suggests leakage of drug from inflamed lung tissue. Clearance is decreased following treatment of acute exacerbations, and similar phenomena are seen in non-CF patients with severe chronic bronchiectasis [19]. That such mechanisms, or others, may be saturable is suggested by the reduction of trimethoprim clearance seen on repeated dosing.
The total body clearance of theophylline in CF patients is approximately twice that of healthy controls. This difference cannot be accounted for by changes in bio-availability or protein binding. Increased formation of theophylline metabolites suggests that it may be due to induction of hepatic microsomal enzyme activity [7]. Similarly, the clearance of lorazepam and indocyanine green, model substrates for glucuronidation and hepatic blood flow, was increased in CF, compared to patients with cancer whose surgical or radiotherapy treatment had not involved the liver [11]. Theophylline clearance increases with disease severity, a picture also seen with gentamicin.
Palliative care
It is not surprising that there is little information available as to the pharmacokinetics of drug treatments in the palliative phase, principally for ethical reasons that are immediately apparent. This is particularly true in the case of children. However, some insight may be gained from changes identified during periods of acute illness [20].
The lung is increasingly recognized as important in the clearance of a number of drugs and chemicals [19], since it receives the entire cardiac output. Acute and chronic pulmonary disease can significantly affect drug disposition, but these changes have been poorly studied in children. The mechanisms are most commonly indirect, rather than direct. Respiratory decompensation results in altered blood flow to major organs, reduced tissue perfusion, hypoxaemia, hyper-capnia, acid-base imbalance, and multiple organ failure. Acute and chronic hypoxia decreases the hepatic clearance of drugs, a phenomenon illustrated by the significantly decreased clearance of theophylline in patients with acute asthma. Hepatic oxidation is decreased in acute pneumonia and chronic obstructive pulmonary disease. Chronic respiratory disease has also been reported to decrease the protein binding of acidic drugs, thereby increasing the volume of distribution [19]. Acidosis, hypoxaemia and hypercarbia have been shown to enhance the penetration of theophylline into the CNS, with the possibility of enhanced toxicity.
Severe acute illness is often accompanied by organ dysfunction, resulting from sepsis, shock, trauma and severe burns, as well as primary diseases of the liver, kidneys, heart or lungs. Pharmacokinetic variables in such situations should not be considered separately from pharmacodynamic ones. It is recognised that in critical illness, the relationship between drug levels and tissue responsiveness is altered for digoxin, ranitidine and cimetidine, and that certain sub-groups of patients may not respond. In palliative care, acute illness may occur in the presence of chronic disease and organ failure.
Acute cardiovascular disease is likely to reduce hepatic and renal blood flow that, together with disturbances of fluid, electrolyte and acid-base balance and protein binding, will lead to an altered pharmacokinetic profile. As discussed previously, the therapeutic range of total drug concentration may be altered. Wide inter-patient variations are also seen, such as the marked variability in plasma clearance of theophylline in patients with pulmonary oedema.
Acute renal failure may be superimposed on physiological immaturity in the young, and chronic renal failure at any age. Changes in drug disposition may be due to compartmental fluid shifts, acid-base imbalance, altered metabolism and decreased plasma protein binding. As renal function declines, the half-life of morphine and its metabolites increases.
As with renal disease, acute liver disease may be superimposed on chronic. Biological tests of liver function correlate poorly with the liver's ability to metabolise drugs, as previously noted. Issues which need to be considered include the first-pass extraction of drugs such as lidocaine, propranolol, labetalol and calcium antagonists, whose hepatic metabolism is flow-dependent, and may be significantly affected by reduced hepatic blood flow due to portosystemic shunts. Significant increases in bio-availability can result.
Malnutrition can decrease the clearance of drugs [2]. Lorazepam clearance in moderately malnourished children with ALL was significantly greater, corrected for body weight, than that in well-nourished controls with ALL [11]. A variety of studies have demonstrated that when children are less than 60% of the standard weight for their age, processes including absorption, disposition, bio-transformation (particularly, oxidative metabolism) and excretion of drugs are affected [21]. In general, chronic malnutrition results in steady-state drug levels that are higher than normal, and the available evidence suggests that the changes in drug handling are reversible when the malnutrition is corrected [22]. As might be expected, toxicity associated with drugs with a narrow
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therapeutic index may be more likely [21]. For example, cardiomyopathy due to anthracyclines may be more common in malnourished children, compared to those who are well-nourished [22]. However, most studies have been carried out in chronic severe malnutrition, and the effect of less severe malnutrition that is of shorter duration is less clear. Similarly, available studies have concentrated on the effect of protein- calorie malnutrition, and have not addressed the effects of micronutrient deficiency.
Drug administration
A stepwise approach to symptom management is essential, to avoid the use of sophisticated but invasive techniques, without exhausting the possibilities offered by conventional treatment strategies [23]. Over-prescribing should be avoided in order to encourage compliance and ensure that new drugs are not added simply to address problems caused by those the patient is already receiving. Constant review is the key to successful management.
Oral administration
As in other therapeutic contexts, the oral route is preferred [24]. Most children are able to take medicines orally. While liquid medicines are increasingly preferred over tablets and capsules, young children are able to take quite large solid dosage forms with appropriate explanation and encouragement.
Nevertheless, by the time palliative care is considered, preferences with respect to oral medication are likely to have become established, and it is an inappropriate time to introduce dosage forms with which the child is not familiar or actively dislikes, unless there is a therapeutic imperative.
A significant proportion of children can be managed with oral medication throughout the palliative period. Successful management of pain will be a priority for family [23] and professionals alike, and the optimal route of administration of morphine is oral [25]. However, while oral absorption during palliative care will often be normal, this is not necessarily so. The patient's state of hydration, bowel motility, and the area available for drug absorption will all have implications for the rate and extent of drug absorption. The formulation of the medicine administered may also be important, since significant amounts of propylene glycol, or sugars such as glucose, mannitol or sucrose may cause diarrhoea and other adverse GI events [24]. Similarly, many licensed and unlicensed liquid formulations of medicines contain significant amounts of alcohol [24]. Whilst the effect of this may not be apparent in the child who is relatively well, it may become significant as the child's condition deteriorates.
During palliative, care patients may have naso-gastric tubes, gastrostomy buttons or other devices through which drug therapy may given. Ileostomies and duodenostomies may also be used, when these offer the easiest methods by which to administer drugs into the GI tract. All of these, however, while offering convenience, have inherent problems. Reluctance on the part of the patient to have such routes accessed can result in a number of medicines being administered at the same time, with the possibility of interactions occurring. There are many documented interactions within the GI tract that reduce the absorption of one or more co-administered drugs. Nor are such interactions limited to those between drug entities. A recent meta-analysis of the published studies has concluded that the evidence favours an interaction between oral phenytoin and continuous naso-gastric feeding [28].
The use of stomas for drug administration is unlikely to be a preferred route, but may become one of few alternatives. The crucial question here is whether the drug will be available to its normal sites of absorption, and if not, whether alternative sites are available lower down the GI tract. Issues of retention and abnormal secretion, and flow of bowel contents, will also need to be assessed, in order to make a judgement as to whether such routes of administration are appropriate.
The most common reasons for medicines not being given orally are vomiting, difficulty in swallowing and decreased level of consciousness [29]. Difficulty or inability to swallow will have a significant effect on both the acceptability of the oral route and its efficacy and safety. Vomiting is unpleasant, and often poorly tolerated. If it occurs soon after drug administration, it can be assumed to have expelled most of the dose administered, but the same cannot be said if it occurs 30 60 min after administration. During that time, significant amounts of the dose may have been absorbed. In the former case, the whole dose may safely be repeated, but in the latter case, the extent to which the patient has been under-dosed is unknown, and any replacement dose becomes a matter of guesswork.
An inability to take medicines orally will often preclude the use of sustained-release preparations that are most commonly, but not exclusively, available as tablets and capsules. Splitting the dose form or crushing or chewing it will often destroy the sustained-release properties of the formulation [25]. However, this is not always the case, and an understanding of the formulation is necessary in order to maximise the benefit the patient obtains. MST granules provide a liquid medicine with sustained-release properties [25], and also offer the possibility of dose titration in increments smaller than is possible by moving between sachets of different strengths.
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Parenteral administration
When one or more of these problems occur, injectable therapy is the most usual alternative considered in palliative care. Some patients may still have an indwelling central venous access device (CVAD) that, provided it has not become blocked, can be used. When using such devices after a period of non-use, it is essential to exercise care to ensure that clots or vegetations on the end of the line are not thrown off by drug delivery. Once in use, standard aseptic precautions are vital, if the patient is not to be exposed to the risk of infection at a time when he or she is particularly vulnerable.
The use of CVAD's means that drugs can often be given as boluses in small volumes over short periods of time, because the tip of the line lies within a major blood vessel. This has the advantage that it is unnecessary for the patient to be connected to extended infusions, giving them greater mobility if they desire it.
By the time palliative care is started, such devices will often have been removed, and the subcutaneous route becomes the most convenient (Table 18.2). Subcutaneous administration has many advantages, including being seen as less invasive than intravenous therapy, not requiring venous access where such access may be difficult or impossible, being easily monitored for local irritation, and being easily re-located if such problems occur. It is also widely acceptable in the community setting, making it possible to manage patients at home when more invasive devices would preclude this. This route is not suitable for all drugs, and can be limited by concentration. Higher concentrations increase the likelihood of local irritation, and also compromise the stability of the infusion, whilst the mixing of up to four drugs in a single syringe increases the risk of physical and chemical incompatibility.
Table 18.2 Drugs that are commonly given subcutaneously | |||||||||||||||
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Drug compatibility
The issue of drug compatibility is complex, and in order to avoid problems, the manufacturer's recommendation should be followed, not least because to do otherwise renders the administration unlicensed. To follow such recommendations is, however, commonly impractical or impossible in paediatric practice, and palliative care in particular.
In palliative care, the use of subcutaneous infusions has become common practice in recent years, but raises a number of difficulties if treatment is to be given both safely and effectively. Palliative care aims to provide a continuous exposure to the therapeutic agent over a prolonged period, and in order to ensure this, the solubility of the drug, in a restricted volume suitable for subcutaneous infusion, and its stability in solution over an extended period, must be addressed. Factors that affect the stability of a drug in solution include pH, concentration, temperature, time, the presence of other drugs, and the material from which the syringe or infusion system is made.
It is important that drugs are prepared and diluted in solutions with which they are compatible, and one of the key determinants of compatibility is pH. A drug that is most stable in an acidic solution will be more stable in Dextrose 5% (ph 4 5) than in Sodium chloride 0.9% (pH 7). Further, drugs are less stable as their concentration in solution, the ambient temperature and the available time for reaction, the infusion time, increase. Thus, whilst diamorphine is the preferred opiate analgesic for subcutaneous infusion because of its greater solubility as compared to morphine [25], it should not be forgotten that exploiting this property to the full tends to compromise the stability of the solution. The use of continuous infusions at ambient temperature raises further problems. A drug that is sufficiently stable at room temperature for an intravenous bolus injection may not be stable enough to permit an infusion over several days (Table 18.3).
There is some literature on the stability of drugs in solution [26, 27], but it should be interpreted with caution. New data is continually reported (www.palliativedrugs.com;www.pallmed.net). Many published reports rely on visual inspection of the solution and the assumption that a lack of evidence of incompatibility, such as precipitation or crystal-lisation, colour change or effervescence, indicates compatibility. This is an oversimplification, since a lack of visual clues to incompatibility indicates only that whatever substances the solution contains are soluble in the volume of fluid available. The original substances in the solution may have decomposed,
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Table 18.3 Stability of commonly used drugs in simple solution [26] | |||||||||||||||||||||||||||||||||||||||||||||
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or reacted to form other inactive or toxic compounds. Studies which report chemical analyses of the solutions tested can provide greater reassurance, but are fewer in number due to the greater technical resources required.
A further difficulty in relating this literature to the clinical situation is the fact that the stability of a drug in solution will be defined by the several variables listed previously. One is very fortunate to find a published study which reports the stability of a solution that matches all these variables. If the patient's circumstance or condition prevents the use of a solution that has been tested, to what extent can data be extrapolated? Can it be assumed that a concentration of 200 mg in 1 ml is stable if a study reports that 20 mg in 1 ml is stable, even if all other variables are matched?
But the greatest difficulty is created by the practice of infusing more than one drug from a single syringe. Whilst the clinical situation may justify such mixing, it is only appropriate if the combination can be shown to retain both efficacy and safety. The majority of the literature on combinations of two, three or four drugs in a single syringe is based on visual rather than analytical assessment, and the use of efficacy as a proxy for stability. Yet such mixtures create increasing potential for interaction by bringing together more chemical entities which may react with each other, and increasing the pressure on the system by, for example,
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increasing the concentration of drug(s) within the available fluid volume. Nor can efficacy be a true proxy for stability, since there is no comparative data of the efficacy of the same drugs and doses given as concurrent but separate infusions.
Notwithstanding the above, the mixing of two or more drugs in the same syringe is an accepted part of palliative care practice, and the number of textbooks [26, 27] and internet sites (www.palliativedrugs.com; www.pallmed.net) which collate reports, varying from the anecdotal to formal studies, provide some reassurance to the practitioner who is faced with no alternative but to infuse a multi-drug mixture (Table 18.4).
Table 18.4 Compatibility of common mixtures in syringe (confirmed by chemical analysis) [26] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Transdermal/transmucosal administration
The oral and subcutaneous routes are appropriate to many clinical situations, but patient preference and the clinical situation may require consideration of other possibilities. The transdermal and transmucosal routes have been used for many years, but have remained within narrowly defined therapeutic situations. Examples include the administration of glyceryl trinitrate by both the transmucosal and transdermal routes, and transmucosal administration of 2 sympathomimetic and corticosteroid in the treatment of asthma and other respiratory conditions [30]. Proliferation of off-label uses of drugs has commonly resulted, as practitioners seek to exploit these routes of administration in a wider range of therapeutic situations.
Drug administration using such routes is not straightforward. Defining safe and effective doses requires an understanding of the mechanism, rate and extent of drug absorption across the membrane and, crucially in the context of palliative
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care, how such parameters are influenced by the patient's state of hydration, skin thickness and so on. These variables can only be defined through clinical studies, but this will never be easy in this patient group.
Many children will be familiar with transdermal drug administration through the use of EMLA cream. The rate and extent of transdermal drug absorption depends on a number of factors, including site of application; thickness and integrity of the stratum corneum epidermidis; size of the molecule; permeability of the membrane of the drug delivery system; state of skin hydration; pH of the drug; drug metabolism by skin flora; lipid solubility; depot effect of drug in skin and variability of blood flow in the skin.
Because skin thickness and blood flow vary with age, controlling the extent of drug uptake is a particular difficulty. Children have a relatively rich blood supply in the skin and thinner skin than adults, so that transdermal absorption defined from adult studies is not necessarily applicable to children. The route may have obvious attractions to children, but experience with drugs such as hexachlorophene, which produced damage to the CNS when used to bath babies with their relatively large body surface area and thin skin, highlights the difficulties.
Examples of transdermal drug delivery familiar to practitioners in palliative care include hyoscine patches for the control of secretions and nausea; fentanyl and buprenorphine patches for pain and topical corticosteroids.
Nevertheless, the potential for toxicity should not be minimised. Excessive absorption through the skin may occur, commonly the result of application to damaged skin. It should not be forgotten that transdermal drug delivery results in systemic drug levels, which may interact with concurrent therapy administered by other routes. Methaemoglobinaemia has been reported in infants treated with EMLA cream. Concurrent administration of drugs such as phenobarbital, phenytoin, paracetamol and sulphonamides, which may also elevate methaemoglobin levels, should be avoided.
The fentanyl patch (Durogesic ) illustrates some of the difficulties associated with this method of drug delivery. In adults, transdermal absorption of fentanyl commences one hour after application of the patch, achieves initial therapeutic levels after 6 8 h peaks at 24 h, and thereafter, slowly declines. Drug accumulates in the skin and produces a depot effect. These characteristics make it difficult to predict the dosage of another opiate analgesic which will be required during the time to peak plasma levels, and also the dosage and schedule for any narcotic prescribed to replace the patch, if this becomes necessary.
Transmucosal administration
Transmucosal drug delivery will also be familiar through the used of local therapy for respiratory diseases [30]. Other uses include inhalation anaesthesia and the delivery of vasoactive drugs such as epinephrine, lidocaine and atropine in resuscitation, sedatives and hypnotics. Mucosal surfaces usually have a rich blood supply, providing the potential for rapid drug absorption and delivery to the systemic circulation. In most cases, first-pass metabolism by the liver will be bypassed.
The amount of drug absorbed will depend on factors including drug concentration; vehicle for drug delivery; mucosal contact time; venous drainage of mucosal tissue; drug ionisation and pH of the site of absorption; size of the drug molecule and lipid solubility.
Licensed drug delivery systems include metered dose aerosols, powder inhalers, nebulisers and vapourisers. Direct instillation of solutions is usually unlicensed. Inhaled drugs are typically deposited in the upper airway, due to their relatively large particle size (> 4 m), but very small particles (0.5 1 m) are also deposited here. To reach the lower airway, a particle size between these limits is required. Water-soluble drugs also tend to remain in the upper airway, while hydrophobic drugs are more likely to reach distal airways. Since drug delivery is by passive diffusion, absorption of fat-soluble drugs will be more rapid than water-soluble ones. Absorption of nebulized morphine is unpredictable, and is best avoided [25].
Potential problems associated with this route of administration include drug metabolism in the respiratory tract; possible conversion to carcinogens; protein binding; mucociliary transport altering drug contact time; local toxic effects such as oedema, and local toxicity due to propellants, carriers or preservatives.
Although the respiratory tract is a common route of drug administration, the nasal mucosa is less often used. Drug applied to the nasal mucosa may be absorbed by olfactory neurons, supporting cells and the capillary bed, and directly into the cerebrospinal fluid (CSF). Transneuronal absorption is slow, whereas absorption by supporting cells and the capillary bed is more rapid. For some drugs administered as a nasal spray, the CSF: plasma concentration is greater than when the drug is administered intravenously or orally. This suggests absorption through the perineural space around the olfactory nerves, which connects directly with the subarachnoid space.
Vasopressin and corticosteroids were amongst the first drugs given by this route. The ability to achieve a rapid response makes it useful for the administration of sedatives and opiates, although the exact route of absorption remains unclear. However, many children object to this method of administration, because of the sensation associated with the volume of solution delivered, and an unpleasant taste in the posterior pharynx.
There is little chance of delayed absorption by the intranasal route, but the possibility of continued absorption of
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swallowed drug needs to be considered. Further, neurotoxicity has been demonstrated following the direct application of ketamine and midazolam to neural tissues. Much remains to be done to identify all the possible risks associated with drug delivery by this route.
Oral transmucosal drug absorption is efficient for reasons similar to those associated with absorption across other mucosal surfaces. Typically, drug appears in the blood within 1 minute, and peak blood levels occur within 10 15 min. Buccal administration of midazolam has been shown to be as effective as rectal diazepam for the control of continuous seizures in children and adolescents [31]. Similarly, a bio-adhesive buccal morphine tablet has been shown to have the same bio-availability as a controlled-release oral tablet [32]. Oral transmucosal absorption has the potential benefit of avoiding drug degradation by gastric acid and first-pass metabolism in the liver. However, a prolonged contact time with the mucosal surface is necessary for significant drug absorption, and the palatability of the formulation will have a significant impact in this respect.
In order to achieve prolonged contact time, drug may either be administered as multiple small aliquots in suitably cooperative patients, or as sustained-release lozenges. Currently licensed for breakthrough pain, although not in children, the Actiq formulation presents fentanyl as a lozenge in which a matrix of drug is fixed to a plastic applicator, providing a formulation which may be sucked, or wiped around the inside of the mouth. The formulation permits simple dose titration, although absorption will be dependent on factors, such as mucosal hydration, that vary significantly over time. It also offers the possibility of reducing the incidence and severity of side effects, such as respiratory depression and glottic and chest wall rigidity, which are commonly seen in patients receiving intravenous fentanyl. Any drug that is swallowed will be destroyed by gastric acid, precluding the possibility of uptake from other potential sites of absorption.
Rectal administration
The rectal route offers a further possibility for transmucosal drug delivery. Suppository and enema formulations of a limited range of drugs have been available for many years, particularly when a local effect is required. Benzodiazepines may be administered by this route for epileptic seizures [30], and antiemetics suppositories are valuable for treating vomiting patients. This route has also been used on paediatric hospital in-patients for whom the oral or intravenous routes were not available, commonly using formulations such as oral liquids or injection solutions not intended for this route. Such use was based largely on anecdotal evidence of efficacy, but there is increasing evidence of the suitability of this route of administration in suitable, compliant patients [33, 34, 35].
The rate of rectal absorption depends on formulation; volume of liquid; drug concentration; site of drug delivery; presence of stool; local pH; period over which drug is retained and differences in venous drainage across the rectosigmoid region. In consequence of these, and the loss of some drug through leakage or expulsion, significant inter-patient variability of drug absorption is seen in practice. Whilst drug absorption may be equivalent to administration of an intravenous bolus, it may conversely be delayed and/or prolonged. In addition, this route may not be appropriate for patients, such as the immuno-compromised, in whom even minor trauma to the rectum can result in abscess formation and prolonged bleeding.
As noted above, drug levels following rectal absorption will be influenced by the delivery of the drug. Drug delivered high into the rectum is subject to hepatic first-pass metabolism, since the superior rectal veins drain this area. Drugs administered lower in the rectum are delivered to the systemic circulation by the inferior and middle rectal veins and bypass such metabolism. The patient's posture and the method of drug delivery will influence drug availability, although the clinical implications of such variability are not well-defined. MST tablets have been successfully administered by the rectal route, although drug absorption is highly dependent on the height of insertion of the tablet. The use of such sustained-release formulations is likely to carry a significant risk of over-dosage, if absorption from one dose form is not complete before another is administered.
However, the concentration of the drug solution is also a key determinant of response. It has been shown that equivalent sedation was achieved with 25 mg/kg of a 10% solution and 15 mg/kg of a 2% solution. Such findings illustrate the need for consistency in the method of delivery, if predictable clinical effects are to be achieved. In general, the rectal dose required for similar clinical effect is higher than the oral or intravenous dose, with slow onset of duration and prolonged duration of effect. Initiation of such treatment, other than single doses, should ideally be managed in an in-patient setting, due to the unpredictability of drug absorption. However in the palliative situation, this will rarely be appropriate.
Unlicensed medicines
The issue of unlicensed medicines has its origins in the thalidomide disaster, and the public demand for stricter controls and safeguards around the pre-clinical testing of drugs.
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The Medicines Act, 1968, addresses all aspects of the marketing, sale and supply of drugs. In the United kingdom, the Medicines Control Agency (MCA), advised by the Committee on the Safety of Medicines (CSM), administers the process by which drugs are licensed and granted a Marketing Authorisation (MA) formerly known as a Product License [36].
A pharmaceutical company wishing to market a medicine must satisfy the MCA that there is sufficient evidence, gained through laboratory testing and clinical studies, that the substance as formulated is both safe and efficacious.
Historically, medicines have been licensed on a national basis, but it is becoming increasingly common for licensing approval to be granted on a Europe-wide basis by the European Medicines Evaluation Agency (EMEA), advised by the Committee on Proprietary Medicinal Products (CPMP).
The MA specifies the indications, patient population, dose, method of administration, contraindications and other precautions in use, as well as other information, and all of this defines the uses for which the manufacturer is permitted to promote the product. This information, central to the original philosophy of the Medicines Act and the licensing process, is seen as crucial to the safe prescribing and administration of medicines. It is made widely available as the Summary of Product Characteristics (SPC), formerly known as the data sheet, in both printed and electronic formats.
Following publication of the Marketing Authorisation Regulations on 1 January 1999, it is now a legal requirement that patient information leaflets (PIL), which must accurately reflect the SPC, be supplied with dispensed medicines [37]. Pharmacists commit an offence under the regulations if a leaflet is not supplied to all hospital out-patients and in the community.
As commercial enterprises, pharmaceutical companies are unlikely to research and develop products for markets that will not provide a return on the considerable financial investment required to obtain an MA. The paediatric market for most drugs is small, and it is widely believed that it is the issue of return in investment which results in many medicines not having an MA for use children, even though such a use might have been anticipated at the time the original MA was sought, or subsequently become apparent.
Because there is no incentive to research and license the use of medicines in this age group, children, in common with some adults, (particularly the elderly), do not have access to modern medicines that are licensed for use in their age group, or for indications for which they are regularly used.
In 1996, only 30% of 103 newly introduced drugs were licensed for use on children [38]. A further 20% clearly had the potential for use in this age group, but were not appropriately licensed, and of these, 50% had already been used in a large children's hospital in the United Kingdom. A similar study from Europe, in 1999, showed that of 45 new drugs, only 20% were licensed for children, even though 45% had such potential [39].
Some attempts have been made to address these issues, but none have made a significant impact to date. The Best Pharmaceuticals for Children Act, 2001, (USA), provides patent exclusivity to drug companies that conduct paediatric studies on new drugs, or those already marketed [40]. Twelve drugs, including baclofen, furosemide, heparin, lorazepam, and spironolactone have been identified for testing in accordance with this legislation, in 2003 [41]. However, the paediatric drug rule, a previous measure introduced by the FDA in 1988, which required all drugs to be studied in children at the same time as they come to market for adults, has recently been declared unlawful by a US District Court [42], despite wide acceptance by the industry, and despite some success in increasing the testing of drugs in children and in increasing the availability of licensed uses in this population.
The possibility that not all medicines would be licensed for all patient groups or therapeutic indications was envisaged, or at least catered for, by the Medicines Act. It permits the prescribing, supply and administration of unlicensed medicines, but this in no way diminishes the responsibility of medical, nursing and pharmacist practitioners to perform their role in an informed and conscientious manner that safeguards the interests and safety of the patient. In fact, that responsibility is increased, because the manufacturer will not be held accountable if a medicine has been used outside the terms of its MA. Recognising two separate issues, the term unlicensed has come to be applied to a situation where the medicinal product is not available as a product with an MA, while off-label is used to describe the use of a licensed product where treatment of the particular patient group, the indication, or the means of administration are not in line with the MA.
There are concerns that unlicensed medicines have not been subject to independent peer review in respect of their quality, efficacy and safety. These concerns are understandable, but in assessing the relative risks of licensed versus unlicensed medicines, it is important to recognise the limitations of the licensing process. When new medicines come to the market, they will have been evaluated in clinical studies involving a relatively small number of patients, who have been rigorously selected on the basis of the inclusion/exclusion criteria set out in the study protocol. Post-licensing use will be in a much wider and less rigorously selected population, and there are many examples of drugs that have been withdrawn soon after marketing, as a consequence of concern about their safety.
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Similarly, the increasing requirement of regulatory bodies for randomised controlled studies against placebo preclude the comparison, at the pre-marketing stage, of a new substance against established treatments, if they exist.
Press comments that in using unlicensed medicines, doctors have to guess the dose in the absence of available information from an MA, ignore the fact that such information in an MA may not be based on experience from a wide patient base, espcially when the drug is new to the market. Similarly, these comments ignore the possibility that the use of unlicensed medicines over a prolonged period may result in the accumulation of both clinical experience and published data that permit the drug to be used both safely and efficaciously.
An MA refers to both the drug and the formulation in which it is supplied. In predominantly aiming their products at the adult market, pharmaceutical manufacturers present their products in formulations, particularly tablets and capsules, which are often inappropriate for children, because of the dose contained within them, their physical size, or their palatability. Pharmacists have historically provided extemporaneously prepared liquid preparations from such formulations, and injections, although such products may increasingly be obtained from commercial sources, when they are known as Specials . However, good quality data on the stability and shelf-life of such products, whatever their source, is often lacking. This is particularly true in the case of those products for which pharmaceutical ingredients are not available, such as treatments for certain metabolic diseases. Neither must it be forgotten that in preparing such presentations, the use of the drug becomes unlicensed , even though the original preparation used may be licensed in respect of both the age group and therapeutic indication.
This creates a tension, amongst all those involved in the case of the patient, between the desire to treat a condition with a medicine or a chemical for which there may be good evidence of efficacy of treatment, and the awareness that they will be held accountable for any harm that befalls the patient in consequence of that treatment. The accountability of health care professionals will inevitably be at a higher level if an unlicensed product, rather than a licensed one, is used.
A number of recent studies, in both the United Kingdom and Europe, have sought to identify the extent of unlicensed and off-label prescribing in both hospital and community settings [43, 44, 45, 46, 47, 48, 49, 50, 51]. In respect of children in hospitals, the extent of unlicensed and off-label use of medicines has been shown to be 25% in a general paediatric ward, 40% in a paediatric ICU and 80% in a neonatal ICU. In the community, 11% of prescribing in the United Kingdom is unlicensed or off-label, while 33% of prescribing is unlicensed or off-label in France.
Such figures raise two questions: is this a problem and, if it is, what should be done about it? Where unlicensed or off-label medicines are prescribed and supplied, and harm results, both the clinical staff involved and their employers may be held liable, unless they can demonstrate that they acted responsibly and in the patient's best interest. It is, therefore, most important that such prescribing is in accordance with the knowledge base available at the time, even though this may be extremely limited where rare conditions or new treatments are concerned. Disclaimers, signed by either the clinician or the patient or carers, almost certainly do nothing to diminish the responsibility of clinical staff to act in the best interests of the patient, whatever their roles in the delivery of care.
Whether the prescribing of unlicensed and off-label medicines does put children at greater risk is unproven, but a nonsignificant trend towards more adverse reactions occurring amongst hospital in-patients prescribed such treatment has been identified [43]. It is likely that at least one factor in any such trend will be the need to calculate and measure the required dose from the original adult dose form.
A further difficulty is the requirement to provide a PIL with each supply to hospital outpatients and patients treated in the community. In the case of off-label prescribing this will result in the patient and family being given incorrect, confusing and misleading information. In the case of unlicensed medicines, PIL's may simply not be available or, if the medicine is imported, may be in a foreign language. To try to explain this situation, a joint committee of the Royal College of Paediatrics and Child Health (RCPCH) and the Neonatal and Paediatric Pharmacists Group (NPPG) have produced a policy statement and information leaflets for both patients/carers and older children, that can be supplied with dispensed medicines, or downloaded from their websites [52].
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