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Drugs in the fetus and newborn infant
8 Drugs in the Fetus and Newborn Infant SANFORD N. COHEN SARASWATHY K. GANAPATHY
Recent advances in pharmacology have led to a better understanding of the factors that must be considered in planning therapeutic regimens for the neonatal patient. In spite of this, the safe and effective use of pharmacologically active agents in newborn infants remains one of the most problematical areas of paediatric practice today (Yaffe, 1972). Drugs have therapeutic effects either by virtue of their ability to alter h u m a n physiology and chemistry, or because they are selectively toxic to invading organisms or to tumour cells. To be an effective systemic therapeutic agent, a drug must first gain access to the body and reach its site of action. To be useful clinically a drug must be eliminated from the body rapidly enough to prevent toxic quantities from building up during a course of therapy. Drugs can be eliminated either by metabolic alteration of their molecules into inactive derivatives prior to excretion or by excretion of the active drug itself. Thus, four basic processes - - absorption, distribution, metabolism and excretion - - govern the clinical effectiveness and safety of therapeutic agents.
ABSORPTION Absorption is the process by which a drug enters the body from its site of administration. During the antenatal period the fetus is exposed to drugs by virtue of their diffusion through the placenta from the maternal circulation. The fully developed h u m a n placenta is of the haemochorial type in which the fetal capillary m e m b r a n e is exposed directly to maternal blood. Diffusion of a drug across the placental membrane is influenced by various physicochemical factors, including ionisation constant, solubility and molecular weight, as well as factors such as the concentration gradient between maternal and fetal sides of the membrane, and protein binding. Other factors which may influence the diffusion of drugs are placental blood flow and pathological changes that may alter the anatomy of the intervillous space (Asling and Way, 1971). It must generally be assumed that any drug administered to the pregnant woman will pass across the placenta and reach the fetus, with the exception of certain very high molecular weight compounds such as heparin and polypeptide hormones such as insulin and oxytocin. Clinics in Endocrinology and Metabolism--Vol.
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Examples of pharmacological effects upon a fetus after drugs have been administered to the mother include: masculinisation of the female fetus by androgenic hormones, hypothyroidism in a newborn infant due to propylthiouracil given to the mother for the treatment of hyperthyroidism, intrauterine death or neonatal haemorrhage due to the use of coumarin anticoagulants, prolonged symptomatic hypoglycaemia following the use of chlorpropamide during pregnancy, and early depression of activity with possible later withdrawal symptoms following the use of a host of tranquillisers, sedatives, and narcotic analgesics. There is great variability in the absorption of drugs by a newborn infant when administered other than by the parenteral route and this route is therefore preferable for systemic therapy. Even with parenteral administration various physiological and anatomical factors govern the absorption of a drug. Factors limiting the value of subcutaneous administration for instance are: the volume that can be administered without compromising the blood flow to overlying skin; the possibility of causing damage to adjacent tissues due to the concentrated or caustic nature of the injected material; and variation in absorption due to poor circulation to peripheral areas. The latter is especially important in sick neonates and in very immature infants whose poor peripheral circulation is compromised further by hypothermia. The skin of the newborn infant is marked by immaturity of the stratum corneum (Solomon and Esterly, 1971) which allows the absorption of topical preparations to a far greater degree than occurs under usual circumstances in more mature patients. There are also potential drawbacks to the use of repeated intramuscular injections in newborn infants such as poor peripheral circulation in sick infants, the number of injections that can be given safely into the small muscle mass of the infant, and the amount of material that can be given in each dose. In spite of these disadvantages, however, the intramuscular route is usually both safe and adequate to provide enough drug in the circulation for the treatment of disease. When a drug is injected intravenously, it bypasses all of the factors that affect absorption and enters the circulation directly. Certain parenteral preparations can lead to untoward effects when given intravenously, however, due to the physical and chemical properties of the active agent as well as the buffers, preservatives and other additives in the preparation. Thus, the use of highly concentrated solutions or those with sclerosing properties can lead to thrombophlebitis or sloughing of tissues from infiltration around the site of injection. The intravenous administration of paraldehyde may lead to acute pulmonary difficulty due to the aggregation of droplets of this waterinsoluble agent within pulmonary blood vessels. The aminoglycoside antibiotics (e.g. kanamycin and streptomycin) may interfere with breathing when administered in high doses intravenously because they have a curariform action at high blood concentrations (Weinstein, 1970). Injection of drugs via umbilical vessel catheters may either cause serious liver damage (umbilical vein) or marked renal or extremity ischaemia (umbilical artery) (Symansky and Fox, 1972). When appropriate precautions are taken, however, the intravenous route is safe for the treatment of seriously ill infants.
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DISTRIBUTION
Drugs which are used clinically are able to pass through body membranes. Thus, for practical purposes, no drug is limited to the intravascular compartment after it has been absorbed. Distribution is the process that leads to the partition of drugs between the various body organs and tissues. The exact distribution of a drug at a given time after a dose depends upon physiological conditions within the patient and the physicochemical properties of the drug itself. For most drugs, if measurements of tissue concentrations are made soon after they are administered, the distribution is found to be almost directly related to the blood flow to the individual organ or tissue (Schanker, 1971). However, the final distribution of a drug (and its concentration in various tissues) is governed by such factors as: the pH of the patient's body fluids, the patient's size and weight, the proportion of the total body water that is intracellular, the drug's lipid solubility, its ionisation constant and the extent to which it is bound to plasma, or to other body proteins (Weber and Cohen, 1975). Thus, final distribution and sites of highest concentration must be determined experimentally. The relationship of plasma protein binding to safe drug therapy is especially important in the newborn infant. Drugs that are absorbed into the circulation are bound to varying degrees to the plasma proteins, especially to albumin. The bound component of a drug is neither pharmacologically active nor readily diffusable. Thus, the molecules that are bound to albumin represent an internal reservoir of the drug. Alterations in the plasma albumin concentration can have a profound effect upon the size of this potential reservoir and upon the concentration of the drug in various tissues. Thus, the relative hypoalbuminaemia of immaturity must be taken into account when suggesting therapeutic regimens for premature infants, or toxic drug concentrations might build up in their tissues due to the small size of their plasma reservoir compartment. When several drugs compete for protein binding sites, the distribution of one or more of them may be altered. The distribution of bilirubin can also be altered when a drug interferes with its protein binding. This drug--bilirubin interaction represents a unique hazard for neonatal patients and is an example of the effect of distribution upon the action of a compound. Premature infants treated with sulfisoxazole (sulphafurazole) develop kernicterus when their serum bilirubin concentrations are well below the usual dangerous range (Silverman et al, 1956). Kernicterus occurs in those infants because bilirubin, displaced from plasma binding sites by the sulphonamide, gains access to the brain where it has a cytotoxie effect (Odell, 1959). METABOLISM
Many antibiotic agents are sufficiently water-soluble at physiological pH to be excreted in the urine in an unchanged form. For example, the various penicillins and the aminoglycoside agents (kanamycin, gentamicin, etc.) can be recovered almost quantitatively in the urine in active form after administration to patients at all stages of development. However, most pharmacological agents are highly lipid-soluble chemical compounds that are
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reabsorbed in the renal tubules after glomerular filtration. Thus, their elimination from the body is greatly impeded and they would persist in high concentration for long periods of time if no other mechanism were available to assist their excretion (Brodie, 1964). These agents are altered within the body by a series of enzymatic drug-metabolising reactions. There are two major categories of drug metabolising reactions: Phase I or non-synthetic reactions (oxidations, reductions, and hydrolyses); and Phase II or synthetic reactions (conjugations). The enzymes that catalyse drug metabolism may be found in vitro in several body tissues, but most drug metabolism in vivo appears to be carried out in the liver.
Non-synthetic Reactions Phase I or non-synthetic reactions consist primarily of oxidations which are carried out by so-called 'mixed function' oxidases that are fixed to the membranes of the microsomes of the endoplasmic reticulum. The various oxidative reactions that drugs undergo in the body involve the transfer of an 'activated' oxygen atom from its carrier protein to the drug molecule (Table 1). These reactions are catalysed by 'terminal' oxidases, which may or may not be identical with the carrier molecule, cytochrome P-450. However, they all depend upon the activity of the electron transport system that generates the P-450-activated oxygen complex. This electron transport system has been found in microsomes from liver as well as from adrenal cortex where it is required to provide activated oxygen for the hydroxylation steps that take place in steroid biogenesis. The P-450 system and the mixed function oxidases have been discussed extensively elsewhere (Gillette et al, 1969; Estabrook, Gillette and Leibman, 1973). Table 1. Phase I drug oxidation and reduction reactions Oxidations
1. 2. 3. 4. 5. 6. 7. 8.
Hydroxylation of aromatic compounds Hydroxylation of alkyl hydrocarbon chains Deamination O-Dealkylation N-Dealkylation N-Oxidation Sulphoxidation Sulphur--oxygen exchange
Reductions
1. Azo-reduction 2. Nitro-reduction
The products of P-450-associated oxidation and of reduction (Table 1) may be pharmacologically less active, equally active, or more active when compared to the parent compound. Furthermore, while the molecules of these products are generally more polar than the original drug, many must undergo conjugation before they are so polar that complete detoxification and speedy elimination from the body are assured.
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Synthetic Reactions The Phase II or synthetic reactions generally result in the conversion of relatively non-polar molecules into highly polar compounds that can be excreted in either the bile or the urine. Table 2 contains a partial list of the synthetic reactions that are important in drug metabolism in man. Many of these are carried out by enzymes that are fixed to the smooth microsomes or to the mitochondria, but others are catalysed by enzymes that are found in solution within the cell's cytoplasm.
Table 2. Phase
H drug metabolism reactions
Acetylation Ethereal sulphate synthesis Glucuronide conjugation Glycine conjugation Mercapturic acid formation Methylation Thiocyanate formation Synthetic reactions generally involve the transfer of a polar moiety from an 'activated' donor molecule to the drug itself or to the metabolite formed in a primary (oxidative or reductive) enzymatic conversion. Thus, glucuronide conjugates of the drugs are formed when glucuronyl moieties are transferred from uridinediphosphateglucuronic acid (UDP glucuronic acid) to the drug (or its metabolite), and acetylated derivatives are formed by the transfer of an acetyl group from acetyl coenzyme A to the drug. The mechanisms of action of the various enzymes that catalyse the synthetic reactions may be quite complex (Cleland, 1967) and may have initial rate equations that contain numerous rate and equilibrium constants (Cleland, 1963). Thus, for example, the enzymatic acetylation of aromatic amine and hydrazine compounds proceeds according to a binary 'ping-pong' mechanism and has kinetic 'constants' that vary as the substrate concentrations are varied systematically (Weber and Cohen, 1967). This kinetic complexity renders studies of the ontogenesis of drug metabolising enzymes very difficult to carry out and to interpret. Another level of complexity is introduced into the study of synthetic reactions by the chemical diversity of the compounds that may be conjugated with the same polar moiety. For example, UDP glucuronic acid, the most versatile of the donors, can interact with enzymes that catalyse the conjugation of at least 16 different chemical groups (Williams, 1959). The number of different conjugating enzymes (transferases) involved in glucuronide conjugation and their specificity for the various chemical groups of receptor molecules are unknown.
Development of Drug Metabolising Capacity Fetus PHASEI. The human fetus is capable of carrying out a number of the oxidative reactions that are associated with drug metabolism at an early stage of intra-
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uterine development. It is difficult to interpret some of the studies quantitatively, however, since whole cells which may contain most of the Phase I activity are present in 'homogenates' of very early fetal liver (Ackermann, Rane and Ericsson, 1972) and the early studies did not include an examination of the low speed centrifugal pellets for activity. Various investigators have found that a number of compounds are oxidised by liver preparations from 12 to 16-week-gestation human fetuses. These compounds include: aminopyrine (amidopyrine) (Yaffe et al, 1970), aniline, and ethylmorphine (Rane and Ackerman, 1972), benzpyrene (Pelkonen et al, 1971a), chlorpromazine (Pelkonen et al, 1971b), desmethylimipramine (desipramine) (Rane et al, 1973), and hexabarbital (hexobarbitone) (Pelkonen, Vorne and K~irki, 1969). Indeed, it has been suggested that some fetuses may metabolise certain drugs more rapidly than some adults. This has led to speculation concerning the possibility that fetal drug metabolism may yield more of a specific metabolite than is produced by the pregnant woman herself (Pelkonen et al, 1973). The fact that a human fetus is capable of carrying out oxidative drug metabolism at an early stage of development has led to concern over the possible side-effects of the metabolites produced early in the second trimester. Thus epoxides, which are potential toxins and teratogens, are produced by fetal hepatic enzyme systems as early as the twelfth week of gestation (Rane and Gustafsson, 1973). The actual effect of such compounds upon fetal development is yet to be determined. Aromatic nitro-group reduction has been detected in human fetal liver homogenates, with p-nitrobenzoic acid as the 'drug' substrate, as early as seven weeks of gestation (Juchau, 1971). PHASE II. Little is known about the early development of synthetic processes in the human fetus, but one report indicates that liver preparations from 19 to 21-week human fetuses failed to catalyse the formation of the glucuronide conjugates of p-nitrophenol, 1-naphthol and 4-methylumbelliferone in vitro (Rane, Sj~qvist, and Orrenius, 1973). Newborn infant Most of the pharmacological studies carried out in human infants to date have been concerned with drugs such as antibiotics which are excreted unchanged in the urine. Thus, they have been mainly pharmacokinetic studies; evaluations of drug metabolism early in extrauterine life have not been carried out extensively. The advent of newer techniques for drug (and drug metabolite) analysis which require only small amounts of blood, however, now makes it possible to study more drugs more completely in neonatal patients. PHASEI. Nortryptyline hydroxylation can be catalysed in the newborn infant. One infant whose mother had taken a large overdose was found to be excreting the hydroxylated metabolite soon after birth (Sj~Sqvist et al, 1972). However, the serum half-life of the drug in this infant was still prolonged. Diphenylhydantoin hydroxylation may be carried out quite efficiently soon after birth according to studies in infants who had been exposed to the drug throughout gestation (Mirkin, 1971; Reynolds and Mirkin, 1973; Rane et al,
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1974). Other studies, carried out after a single dose to infants who had been unmedicated in utero, indicate that the metabolism noted was the result of normal neonatal hepatic function and not due to enzyme induction by the drug acquired transplacentally (Jailing et al, 1970). Hydroxylation of diazepam to form oxazepam proceeds very slowly in the newborn infant (Mandelli et al, 1975). Oxidative N-demethylation of diazepam is carried out more rapidly than hydroxylation. These data were derived from infants who acquired the drug transplacentally following either single or repeated doses to the pregnant woman at term. The metabolite, N-demethyldiazepam, retains much of the pharmacological activity of the parent compound and is excreted quite slowly by the newborn infant (Mandelli et al, 1975). The oxidative metabolism of a number of other drugs has been studied in newborn infants. These drugs include acetanalide (Vest and Streiff, 1959), tolbutamide (Nitowsky, Matz and Berzofsky, 1966), and mepivacaine (Meffin, Long and Thomas, 1973). In all cases the production of the oxidative metabolite appeared to proceed at a much slower rate in the infant than in older children or in adults. PHASE I1. Newborn infants fail to conjugate bilirubin with glucuronide efficiently during the first few days of life. Similarly, there is a failure to form the N-glucuronide of chloramphenicol early in postnatal life and unfortunate results can occur when this development-related difference in metabolic capacity is not considered clinically (Weiss, Glazko and Weston, 1960). Glucuronide conjugates of N-demethyldiazepam and oxazepam, the two main products of Phase I metabolism of diazepam, are formed and excreted more slowly in premature infants than in full-term infants and the latter excrete the glucuronide conjugates of these compounds much less rapidly than do older children (Morselli et al, 1973). Glucuronide and sulphate conjugates of the product of diphenylhydantoin hydroxylation (Phase I) are found in the urine of newborn infants after they receive the drug transplacentally, but they appear to be formed quite slowly in infants when compared to adults (Reynolds and Mirkin, 1973). Both the glucuronide and the glycine conjugates of salicylate are formed quite slowly by newborn infants (Garrettson, Procknal and Levy, 1975). Sulphadiazine is eliminated by premature and full-term infants more slowly than by older infants and children (Fichter and Curtis, 1956). This is probably related to slower conversion of the drug to its conjugated metabolite, N-4-acetyl sulphadiazine. This delayed excretion of drugs that are usually conjugated with an acetyl group prior to elimination has been corroborated recently in several infants who received isoniazid transplacentally (Miceli et al, 1975). The rate of elimination of the antituberculosis agent was so markedly prolonged in these infants that it fell far outside of the usual limits for the genetically determined 'slow acetylator' adults. EXCRETION
Most drugs and drug metabolites are eliminated from the body in the urine. The rate of excretion of drugs in the urine may be limited by the ability of the
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kidney to filter and excrete them. Since drug metabolism proceeds very slowly and renal blood flow, glomerular filtration rate and tubular function are all diminished in newborn infants, the urinary excretion of drugs is generally delayed during the neonatal period. When newborn infants are to be given drugs that are excreted unchanged in the urine, such as the penicillins and the aminoglycoside antibiotics (e.g. streptomycin, kanamycin), the dose must be adjusted for the tendency of these drugs to accumulate within the body. This will minimise the possibility that toxic concentrations will be reached in the patient. Some drugs reach high concentrations in the bile and are eliminated in the faeces. Nafcillin, a semisynthetic penicillin, is eliminated in this way, but still tends to build up in the newborn infant when large doses are administered. This indicates either that biliary excretion is diminished or that enterohepatic recirculation is increased during the neonatal period (O'Connor et al, 1964). COMMENT Some of the doses and regimens recommended for use in newborn infants have been derived from information on the pharmacokinetics of the drugs in newborn infants, while others are recognised to be safe and effective for use in newborns because of empirical observations gathered over many years. These are the only two bases for recommending drug doses for the most immature patients. It is no longer acceptable to use the commonly available formulae related, for instance, to adult weight to derive such doses, since we know now that the effect of a drug in the body is governed by its distribution, metabolism and excretion, rather than by the weight or size of the patient. Physicians who treat newborn infants must resist the temptation to use new drugs in their patients indiscriminately until there are data available to guide them. The constraints placed upon human experimentation by ethical considerations have made the investigation of new drugs for introduction into the pharmacopoeia for neonatal patients especially difficult. If objective pharmacological, therapeutic and toxicological data are to be gathered so that newer agents may be useful for future patients, physicians who have to use such drugs out of therapeutic necessity should endeavour to study as many parameters of drug usage as possible and follow up their patients for as long as possible.
SPECIFIC GROUPS OF DRUGS Antibiotics The penicillins Penicillin G is effective against infections caused by all gram-positive cocci that do not produce penicillinase, most gram-positive bacilli, some gramnegative cocci, and the spirochaetes. It is frequently administered along with an agent that is effective against gram-negative bacilli in the therapy of sepsis neonatorum, especially when the causative organism has not been identified.
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Penicillin G is excreted in the urine, mainly as the biologically active compound. Thus, excretion is the main factor that controls serum levels of penicillin and metabolism can be ignored in determining the appropriate dose. However, the renal clearance of penicillin is markedly diminished in newborn infants (Barnett et al, 1949) and, following small doses of this drug, higher, more sustained blood levels are found in such patients than in older children. Six hours after an intramuscular dose of 22 000 units/kg, the mean serum level in full-term infants is 5.45 units/ml, while in children from 3 to 13 years of age it is only 0.005 units/ml. A daily dose of 50 000 units/kg, administered intramuscularly in divided doses every 12 hours, is sufficient to achieve a therapeutic effect in neonates (Huang and High, 1953). Penicillin is usually administered to newborn infants by the intramuscular route, but when intravenous infusions are used to provide required fluids and electrolytes, the intravenous route may be less traumatic to the patient and should be used. Penicillin may be absorbed quite efficiently from the gastrointestinal tract by some newborn infants (Huang and High, 1953). However, oral administration of penicillin during the neonatal period should be discouraged since reliable absorption should be assured in all infants who require therapy. SEMISYNTHETICPENICILL1NS.Methicillin or oxacillin can be used for the treatment of neonatal infections caused by penicillinase-producing organisms. The former should be avoided in areas where methicillin-resistant staphylococci are common. Cloxacillin and dicloxacillin may displace bilirubin at therapeutic concentrations and should not be used in jaundiced infants (Odell, 1973). Ampicillin, another semisynthetic penicillin, is not effective against penicillinase-producing organisms but has a broader antibacterial spectrum than other penicillins and may be effective against many gramnegative bacilli. Some authors suggest that ampicillin be used instead of penicillin G in the therapy of neonatal sepsis of unknown aetiology (Gotoff and Behrman, 1970). Compared with older children and adults, newborn infants show delay in reaching adequate blood concentrations of the oral penicillins, presumably due to delayed absorption (Cohen et al, 1975). The excretion of all of these drugs and the factors that govern their serum levels are similar to penicillin G (Boe et al, 1967).
The cephalosporins The members of this group of antibiotics bear a strong resemblance to the penicillins in chemical structure, mechanism of action and low potential for toxic reactions. The cephalosporins have a broader spectrum than most penicillins, however, and are effective against gram-negative bacilli and against penicillinase-producing staphylococci. Cephatothin is the most commonly used drug in this group. It is not considered to be the first-choice drug in the treatment of any disease, but its low toxicity and broad spectrum make it a useful drug for the treatment of infections in neonates that are due to Escherichia coli which are resistant to both kanamycin and ampicillin. Since cephalosporins are excreted in the same manner as the penicillins, low doses can be used to produce prolonged therapeutic serum levels (Sheng,
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Huang and Promadhattavedi, 1964). Staphylococci that produce penicillinase may adapt to the presence of cephalosporins by producing a cephalosporinase. Thus, the cephalosporins should not be relied upon in the prolonged treatment of serious illness due to penicillin-resistant staphylococci.
The aminoglycosides This group includes kanamycin, gentamicin, streptomycin and neomycin. They are all potent antibacterial drugs that must be given parenterally when used for the treatment of systemic disease because they are not absorbed from the gastrointestinal tract. Kanamycin is effective against many of the gram-negative organisms that are commonly pathogenic in the newborn infant. It is less toxic in the newborn infant than other drugs that have a similar antibacterial spectrum and in conjunction with penicillin is the combination of choice for the treatment of sepsis of unknown aetiology in this age group. It may be used to eliminate enteropathogenic strains of E. coli from the gastrointestinal tract and should be administered orally when used for this purpose. Gentamicin has an even broader antibacterial spectrum than kanamycin and is especially useful for the treatment of infections due to 'resistant' pseudomonas. It should be reserved for the treatment of pseudomonas infections or diseases caused by other gram-negative organisms that are resistant to kanamycin and ampicillin. Streptomycin has no intrinsic advantage over kanamycin, is more toxic than this widely used drug and is not recommended for the treatment of sepsis neonatorum. However, streptomycin is still used to treat congenital tuberculosis, especially in combination with isoniazid. Neomycin, once the drug of choice for the treatment of diarrhoea caused by the enteropathogenic strains of E. coli and for the eradication of these organisms from asymptomatic carriers, is no longer preferred because of the emergence of many resistant strains. It should be administered only via the oral route (when it is used) because of its potential to produce serious toxicity when it is given parenterally. The serum half-life of kanamycin is 8.9 hours in premature infants, and two hours in adults (Axline and Simon, 1964). This prolongation of half-life is due to the fact that the aminoglycosides are excreted in the urine by filtration and immature infants have a diminished glomerular filtration rate. Therapeutically effective serum concentrations of kanamycin (15 to 25 /~g/ml) may be produced and maintained in some newborn infants, without the production of significant toxicity, by the intramuscular administration of 7.5 mg/kg every 12 hours, but newer data indicate that 10 mg/kg may be more appropriate for some patients (Howard and McCracken, 1975). The aminoglycosides may be toxic to the eighth cranial nerve, leading to vertigo or deafness, or toxic to the kidney, leading to proteinuria and azotaemia. Ototoxicity does not appear to occur in immature infants who are treated with the recommended doses of kanamycin for up to 14 days (Eichenwald, 1966). Proteinuria, cylindruria and mild azotaemia may occur in some infants after the first few days of kanamycin therapy and the
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administration of the drug should be stopped if they appear. There is no evidence that permanent renal damage results if the nephrotoxic effects are discovered early and the drug is discontinued promptly.
The polymixins Colistin (polymixin E) is the only member of this group of antibiotics recommended for use in newborn infants. Its use should be limited to the treatment of infections caused by organisms resistant to other antibiotics, since it has a narrow margin of safety. It is sometimes given orally to eradicate enteropathogenic E. coli, but it is not the drug of choice for this purpose. Colistin is excreted unchanged in the urine but, in contrast to other antibiotics, its serum half-life in the newborn does not differ significantly from its half-life in adults (Axline, Yaffe and Simon, 1967). The basis for this apparent paradox has not been explained as yet. A dose as low as 1.5 m g / k g / d a y administered in divided doses intramuscularly every 12 hours has been found to be effective for the treatment of infections in newborn infants. However, the drug is nephrotoxic and urinalyses and tests for azotaemia must be performed every few days during therapy. In all cases, the course of therapy with colistin should not exceed seven to eight days.
Isoniazid This is the most widely used tuberculostatic agent. It has been recommended for the treatment of overt disease, for the treatment of asymptomatic tuberculin reactors and even for prophylaxis in infants who are likely to be exposed repeatedly to persons with active tuberculosis (Avery and Wolfsdorf, 1968). Isoniazid is recommended as one drug in the combination of choice for the treatment of overt congenital tuberculosis and should be part of any therapeutic regimen for tuberculosis in the neonatal period. No serious toxic reactions have been reported to occur in newborn infants after isoniazid administration, but since this drug is not metabolised rapidly by newborn infants, it cannot be excreted efficiently, and blood levels may tend to build up to a dangerous degree in some infants (Cohen and Weber, 1969; Miceli et al, 1975). Thus, its safety in the newborn infant has not been established firmly enough to recommend that it be administered prophylactically during the first month of life.
Cardiac Glycosides Congestive heart failure and paroxysmal supraventricular tachycardia are currently the only two indications for the use of digitalis preparations in newborn infants. Current concepts of the pathophysiology of respiratory distress syndrome and hydrops fetalis indicate that there is no rational basis for the administration of digitalis glycosides in these conditions. Digoxin is the digitalis glycoside of choice for the treatment of neonates. This is because it is absorbed well, acts rapidly and is excreted in a relatively short time. Thus, a therapeutic regimen can be planned rigorously, rapid
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results can be expected once therapy is begun, and any toxic effects that occur during therapy will diminish rapidly when the dose is readjusted. Digoxin is e!iminated from the body in the urine in the active form. There may be a delay in the excretion of the drug after it is administered to newborn infants due to their hepatic and renal immaturity (Soyka, 1972). Furthermore, there may be increased myocardial sensitivity to the effects of digitalis glycosides in the newborn period. The recommended dose of digoxin for newborn infants is therefore slightly lower than that in older infants (Rutkowski, Cohen and Doyle, 1973). Anticonvuisants and Sedatives
Phenobarbital (phenobarbitone) is the most commonly used member of this group of drugs for treating newborn infants. The indications for its use include seizures and neonatal drug withdrawal symptoms. Seizures due to hypoglycaemia or other metabolic derangements should be treated by correcting the underlying metabolic abnormality. Phenobarbital is very effective in reducing or stopping the irritability that is characteristic of infants of narcoticaddicted mothers. In some centres, phenobarbital is administered to prevent the development of hyperbilirubinaemia or to treat those infants who are already jaundiced (Maurer et al, 1968; Trolle, 1968). The action of phenobarbital in this situation depends upon its ability to induce the activity of the enzyme that catalyses the conjugation of bilirubin with glucuronic acid in the liver (Stern et al, 1970). However, since this drug acts to increase the activity of many enzymes in th/e~body, it may have widespread effects that have not been defined to date. Therefore, it should not be used freely during the neonatal period in the absence of seizures or of a history of maternal addiction. Chlorpromazine can be administered instead of phenobarbital to alleviate the symptoms of neonatal narcotic withdrawal. It is not an anticonvulsant, however, and should not be prescribed for the treatment of convulsant seizures. Diazepam (injectable Valium) has been recommended as an anticonvulsant (Rose and Lombroso, 1970) and for the management of neonatal drug withdrawal (Nathenson, Golden and Litt, 1971). However, it has not been shown to be clearly superior to phenobarbital or paraldehyde for treating seizures during the newborn period and is probably no more effective in controlling withdrawal symptoms than phenobarbital or chlorpromazine. Furthermore, it contains a substantial amount of benzoate, an ion that is known to displace bilirubin from its binding sites on albumin (Cohen and Fern, 1972). A recent report indicates that this effect may not be significant clinically (Nathenson, Cohen and McNamara, 1975). Further investigations should be carried out to evaluate whether parenteral diazepam may predispose certain infants to bilirubin encephalopathy before it is used widely to treat infants during the first week of life. Paregoric, camphorated tincture of opium, has been used widely in the past to treat drug withdrawal in the newborn period, but should be eliminated from our list of therapeutic agents since the camphor in it is
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potentially dangerous and has no therapeutic value. Tincture of opium, diluted to yield 0.4 per cent opium, should be used in its place (Neumann and Cohen, 1975). Opiates should not be used in the treatment of diarrhoea in young inf~/nts, however, since they do not suppress fluid losses in such an instance and may only mask the severity of these losses. Diuretics The indications for diuretic therapy during the neonatal period include congestive heart failure and suspected acute renal failure. In the first instance, diuretics are used as adjuncts to digoxin therapy and in the second, as part of a therapeutic trial to determine whether fluid intake should be restricted or not. Ethacrynic acid and furosemide (frusemide) act mainly upon the reabsorption of sodium in the loop of Henle. Their action is not as dependent upon the glomerular filtration rate as is that of mercurial diuretics and they may act very rapidly, even during the neonatal period. However, both of these drugs can inhibit the binding of small molecules by albumin and are therefore potentially hazardous if given to jaundiced infants during the first few weeks of life (Sellers and Koch-Weser, 1971; Shankaran and Poland, 1975). The thiazide diuretics should not be used to treat infants during the first week of life, since they are inefficient in the presence of diminished glomerular filtration rate and may displace bilirubin from its albumin binding sites (Cohen and Ganapathy, 1973). Furthermore, they are photosensitising agents and might cause adverse reactions among infants who are treated with phototherapy. It is also possible that their carbonic anhydrase inhibiting activity can prolong the period of recovery from birth asphyxia, especially in very small premature infants. In the event that a therapeutic trial with a diuretic agent is indicated to define the state of an infant's renal function, an osmotic agent such as mannitol should be the first choice during the first week of life. Thereafter, one of the potent agents mentioned above (ethacrynic acid or furosemide) should probably be used. CONCLUSION Although the use of drugs to treat the most immature patients safely is less of a problem to paediatricians today than ever before, developmental pharmacology has not yet reached a stage where clinicians can depend routinely upon the safety for newborn infants of new therapeutic agents that are introduced into general clinical use. There will have to be a great increase in our knowledge of neonatal physiology and of the interaction of drugs with the infant's physiological systems before new drugs can be introduced with rational recommendations for use in the neonatal field. The drugs mentioned in this chapter will provide for most clinical situations so that there will be little need to use newer drugs in infants before appropriate studies have been completed.
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REFERENCES Ackermann, E., Rane, A. & Ericsson, J. L. E. (1972) The liver microsomal monooxygenase system in the human fetus: distribution in different centrifugal fractions. Clinical Pharmacology and Therapeutics, 13, 652-662. Asling, J. & Way, E. L. (1971) Placental transfer of drugs. In Fundamentals of Drug Metabolism and Drug Disposition (Ed.) La Du, B. N., Mandel, H. G. & Way, E. L. Baltimore: Williams and Wilkins. Avery, M. E. & Wolfsdorf, J. (1968) Diagnosis and treatment: Approaches to newborn infants of tuberculous mothers. Pediatrics, 42, 519. Axline, S. G. & Simon, H. J. (1964) Clinical pharmacology of antimicrobials in premature infants: I. Kanamycin, streptomycin and neomycin. In Antimicrobial Agents and Chemotherapy, p. 135. Ann Arbor: American Society for Microbiology. Axline, S. G., Yaffe, S. J. & Simon, H. J. (1967) Clinical pharmacology of antimicrobials in premature infants: II. Ampicillin, methicillin, oxacillin, neomycin, and colistin. Pediatrics, 39, 97. Barnett, H. L., McNamara, H., Shultz, S. & Tompsett, R. (1949) Renal clearances of sodium penicillin G, procaine penicillin G, and inulin in infants and children. Pediatrics, 3, 418. Boe, R. W., Williams, C. P., Bennett, J. V. & Oliver, T. K. (1967) Serum levels of methicillin and ampicillin in newborn and premature infants in relation to postnatal age. Pediatrics, 39, 194. Brodie, B. B. (1964) Of mice, microsomes and man. Pharmacologist, 6, 12. Cleland, W. W. (1963) The kinetics of enzyme-catalyzed reactions with two or more substrates or products. I. Nomenclature and rate equations. Biochimiea et Biophysiea Acta, 67, 104-137. Cleland, W. W. (1967) Enzyme kinetics. Annual Review of Biochemistry, 36, 77-112. Cohen, M. D., Raeburn, J. A., Devine, J., Kirkwood, J., Elliot, B., Cockburn, F. & Forfar, J. O. (1975) Pharmacology of some oral penicillins in the newborn. Archives of Disease in Childhood, 50, 230. Cohen, S. N. & Fern, L. M. (1972) The displacement of albumin-bound bilirubin by benzoate: A hazard of the use of diazepam in newborn infants. Pediatric Research, 6, 144. Cohen, S. N. & Ganapathy, S. K. (1973) Unpublished observations. Cohen, S. N. & Weber, W. W. (1969) Newborn infants of tuberculous mothers - - further comment. Pediatrics, 43, 303 (letter to Editor). Cohen, S. N., Baumgartner, R., Steinberg, M. S. & Weber, W. W. (1973) Changes in the physieochemical characteristics of rabbit liver N-acetyl-transferase during postnatal development. Biochimica et Biophysica Acta, 304, 473-481. Eichenwald, H. F. (1966) Some observations on dosage and toxicity of kanamycin in premature and full term infants. Annals of the New York Academy of Sciences, 132, 984. Estabrook, R. W., Gillette, J. R. & Leibman, K. C. (1973) The Second International Symposium on Microsomes and Drug Oxidations. Drug Metabolism and Disposition, 1, 1-486. Fichter, E. G. & Curtis, J. A. (1956) Sulfonamide administration in newborn and premature infants. Pediatrics, 18, 50-58. Garrettson, L. K., Proeknal, J. A. & Levy, G. (1975) Fetal acquisition and neonatal elimination of a large amount of salicylate. Study of a neonate whose mother regularly took therapeutic doses of aspirin during pregnancy. Clinical Pharmacology and Therapeutics, 17, 98-103. Gillette, J. R., Conney, A. H., Cosmides, G. J., Estabrook, R. W., Fouts, J. R. & Mannering, G. J. (1969) Microsomes and Drug Oxidations. New York: Academic Press. Gotoff, S. P. & Behrman, R. E. (1970) Neonatal septicemia. Journal of Pediatrics, 76, 142. Howard, J. B. & MeCraeken, G. H. Jr (1975) Reappraisal of kanamycin usage in neonates. Journal of Pediatrics, 86, 949-956. Huang, N. N. & High, R. H. (1953) Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. Journal o f Pediatrics, 42, 657. Jalling, B., Bor~us, L.-O., Rane, A. & Sj6qvist, F. (1970) Plasma concentrations of diphenylhydantoin in young infants. Pharrnacologia Clinica, 2, 200-202.
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Juchau, M. R. (1971) Drug biotransformation in the human fetus. Nitro group reduction. Archives Internationales de Pharmacodynamie et de Thdrap&, 194, 346-358. Mandelli, M., Morselli, P. L., Nordio, S., Pardi, G., Principi, N., Sereni, F. & Tognoni, G. (1975) Placental transfer of diazepam and its disposition in the newborn. Clinical Pharmacology and Therapeutics, 17, 564-572. Maurer, H. M., Wolff, J. A., Finster, M., Poppers, P. J., Pantuck, E., Kuntzman, R. & Conney, A. H. (1968) Reduction in concentration of total serum bilirubin in offspring of women treated with phenobarbital during pregnancy. Lancet, if, 122. Meffin, P., Long, G. J. & Thomas, J. (1973) Clearance and metabolism of mepivacaine in the human neonate. Clinical Pharmacology and Therapeutics, 14, 218-225. Miceli, J., Olson, W., Weber, W. W. & Cohen, S. N. (1975) Unpublished observations. Mirkin, B. L. (1971) Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism and possible teratogenic effects. Journal of Pediatrics, 78, 329-337. Mitani, F., Alvares, A. P., Sassa, S. & Kappas, A. (1971) Preparation and properties of a solubilized form of cytochrome P-450 from chick embryo liver microsomes. Molecular Pharmacology, 7, 280-292. Morselli, P. L., Principi, N., Tognoni, G., Reali, E., Belvedere, G., Standen, S. M. & Sereni, F. (1973) Diazepam elimination in premature and fullterm infants and children. Journal of Perinatal Medicine, 1, 133-141. Nathenson, G., Cohen, M. I. & McNamara, H. (1975) The effect of Na benzoate on serum bilirubin of the Gunn rat. Journal of Pediatrics, 86, 799-803. Nathenson, G., Golden, G. S. & Litt, I. F. (1971) Diazepam in the management of the neonatal narcotic withdrawal syndrome. Pediatrics, 48~ 523. Neumann, L. L. & Cohen, S. N. (1975) The neonatal narcotic withdrawal syndrome. A therapeutic challenge. Clinics in Perinatology, 2, 99-109. Nitowsky, H. M., Matz, L. & Berzofsky, J. A. (1966) Studies on oxidative drug metabolism in the fullterm newborn infant. Journal of Pediatrics, 69, 1139-1149. O'Connor, W. J., Warren, G. H., Mandala, P. S., Edrada, L. S. & Rosenman, S. B. (1964) Serum concentrations of nafcillin in newborn infants and children. In Antimicrobial Agents and Chemotherapy, p. 188. Ann Arbor: American Society for Microbiology. Odell, G. B. (1959) The dissociation of bilirubin from albumin and its clinical implications. Journal of Pediatrics, 55, 268. Odell, G. B. (1973) Personal communication. Pelkonen, O., Vorne, M. & K~trki, N. T. (1969) Drug-metabolizing activity in the liver, intestine and kidney of human foetus. Acta Physiologica Scandinavica, 77 (Supplement), 330-369. Pelkonen, 0., Vorue, M., Arvela, P., Jouppila, P. & K~irki, N. T. (1971a) Drug metabolizing enzymes in human fetal liver and placenta in early pregnancy. Scandinavian Journal of Clinical and Laboratory Investigation, 27 (Supplement 116), 7. Pelkonen, O., Vorue, M., Jouppila, P. & K/irki, N. T. (1971b) Metabolism of chlorpromazine and p-nitrobenzoie acid in the liver, intestine, and kidney of the human foetus. Acta Pharmacologica et Toxicologiea, 29, 284-294. Pelkonen, O., Kaltiala, E. H., Larmi, T. K. I. & Kiirki, N. T. (1973) Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clinical Pharmacology and Therapeutics, 14, 840-846. Rane, A. & Ackermann, E. (1972) Metabolism of cthylmorphine and aniline in human fetal liver. Clinical Pharmacology and Therapeutics, 13, 663-670. Rane, A. & Gustafsson, J. A. (1973) Formation of a 16,17-transglycolic metabolite from a 16-dehydro-androgen in human fetal liver mierosome. Clinical Pharmacology and Therapeutics, 14, 833-839. Rane, A., Sj6qvist, F. & Orrenius, S. (1973) Drugs and fetal metabolism. ClinicalPharmacology and Therapeutics, 14, 666-672. Rane, A., Garle, M., Borga, O. & Sj~qvist, F. (1974) Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clinical Pharmacology and Therapeutics, 15, 39-45. Rane, A., von Bahr, C., Orrenius, S. & Sj6qvist, F. (1973) Drug metabolism in the human fetus. In InternationalSymposium on FetalPharmacology (Ed.) Bor6us, L. O. pp. 287-303. New York: Raven Press.
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Reynolds, J. W. & Mirkin, B. L. (1973) Urinary corticosteroid and diphenylhydantoin metabolite patterns in neonates exposed to anticonvulsant drugs in utero. Clinical Pharmacology and Therapeutics, 14, 891-897. Rose, A. L. & Lombroso, C. T. (1970) Pathological and electroencephalographic features in 137 full term babies with a long term follow-up. Pediatrics, 45, 404. Rutowski, M. M., Cohen, S. N. & Doyle, E. F. (1973) Drug therapy of heart disease in pediatric patients. If. The treatment of congestive heart failure in infants and children with digitalis preparations. American Heart Journal, 86, 270-275. Schanker, L. S. (1971) Drug absorption. In Fundamentals of Drug Metabolism and Drug Disposition (Ed.) La Du, B. N., Mandel, H. G. & Way, E. L. Baltimore: Williams and Wilkins. Sellers, E. M. & Koch-Weser, J. (1971) Kinetics and clinical importance of displacement of warfarin from albumin by acidic drugs. Annals of the New York Academy of Sciences, 179, 213. Shankaran, S. 8/Poland, R. L. (1975) The displacement of bilirubin from albumin by furosemide. Pediatric Research, 9, 370. Sheng, K. T., Huang, N. N. & Promadhattavedi, V. (1964) Serum concentration of cephalothin in infants and children and the placental transmission of the antibiotic. In Antimicrobial Agents and Chemotherapy, p. 200. Ann Arbor: American Society for Microbiology. Silverman, W. A., Andersen, D , H., Blanc, W. A. & Crozier, D. N. (1956) Difference in mortality rate and incidence of kernicterus among premature infants alloted to two prophylactic antibacterial regimens. Pediatrics, 18, 614. Sj~qvist, F., Bergfors, P. G., Borga, O., Lind, M. & Ygge, H. (1972) Plasma disappearance of nortriptyline in a newborn infant following placental transfer from an intoxicated mother: Evidence for drug metabolism. Journal of Pediatrics, 80, 496-500. Solomon, L. M. & Esterly, N. B. (1971) Neonatal dermatology. I. The newborn skin. Journal of Pediatrics, 77, 888. Soyka, L. F. (1970) Isolation and characterization of reduced nicotinamide adenine dinucleotide phosphate: ferricytochrome c oxidoreductase and identification of cytochrome b5 in the liver of human infants. Biochemical Pharmacology, 19, 945-951. Soyka, L. F. (1972) Clinical pharmacology of digoxin. Pediatric Clinics of North America, 19, 240. Stern, L., Khanna, N. N., Levy, G. & Yaffe, S. J. (1970) Effect of phenobarbital on hyperbilirubinemia and glucuronide formation in newborns. American Journal of Diseases of Children, 120, 26. Symansky, M. R. & Fox, H. A. (1972) Umbilical vessel catheterization: Indications, management and evaluation of the technique. Journal of Pediatrics, 80, 820. Trolle, D. (1968) Decrease of total serum bilirubin concentration in newborn infants after phenobarbital treatment. Lancet, if, 705. Vest, M. F. & Streiff, R. R. (1959) Studies on glucuronide formation in newborn infants and older children. American Journal of Diseases of Children, 98, 688-693. Weber, W. W. & Cohen, S. N. (1967) N-acetylation of drugs: isolation and properties of an N-acetyltransferase from rabbit liver. Molecular Pharmacology, 3, 266-273. Weber, W. W. & Cohen, S. N. (1975) Aging effects and drugs in man. In Handbook of ExperimentalPharmacology, Vol. XXVIII/3. (Ed.) Eichler, O., Farah, A., Herken, H. & Erich, A. D. New York: Springer Verlag. Weinstein, L. (1970) The Pharmacological Basis of Therapeutics (Ed.) Goodman, L. S. & Gilman, A. 4th edition, p. 1287. New York: Macmillan. Weiss, C. F., Glazko, A. J. & Weston, J. K. (1960) Ct'doramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in excessive doses. New England Journal of Medicine, 262, 787-794. Williams, R. T. (1959) Detoxication Mechanisms, 2nd edition. New York: John Wiley. Yaffe, S. J. (1972) Pediatric pharmacology. Pediatric Clinics of North America, 19, 1-256. Yaffe, S. J., Rane, A., Sj6qvist, F., Bor6us, L. O. & Orrenius, S. (1970) The presence of a monocygenase system in human fetal liver microsomes. Life Sciences, 9, 1189-1200.
Recent advances in pharmacology have led to a better understanding of the factors that must be considered in planning therapeutic regimens for the neonatal patient. In spite of this, the safe and effective use of pharmacologically active agents in newborn infants remains one of the most problematical areas of paediatric practice today (Yaffe, 1972). Drugs have therapeutic effects either by virtue of their ability to alter h u m a n physiology and chemistry, or because they are selectively toxic to invading organisms or to tumour cells. To be an effective systemic therapeutic agent, a drug must first gain access to the body and reach its site of action. To be useful clinically a drug must be eliminated from the body rapidly enough to prevent toxic quantities from building up during a course of therapy. Drugs can be eliminated either by metabolic alteration of their molecules into inactive derivatives prior to excretion or by excretion of the active drug itself. Thus, four basic processes - - absorption, distribution, metabolism and excretion - - govern the clinical effectiveness and safety of therapeutic agents.
ABSORPTION Absorption is the process by which a drug enters the body from its site of administration. During the antenatal period the fetus is exposed to drugs by virtue of their diffusion through the placenta from the maternal circulation. The fully developed h u m a n placenta is of the haemochorial type in which the fetal capillary m e m b r a n e is exposed directly to maternal blood. Diffusion of a drug across the placental membrane is influenced by various physicochemical factors, including ionisation constant, solubility and molecular weight, as well as factors such as the concentration gradient between maternal and fetal sides of the membrane, and protein binding. Other factors which may influence the diffusion of drugs are placental blood flow and pathological changes that may alter the anatomy of the intervillous space (Asling and Way, 1971). It must generally be assumed that any drug administered to the pregnant woman will pass across the placenta and reach the fetus, with the exception of certain very high molecular weight compounds such as heparin and polypeptide hormones such as insulin and oxytocin. Clinics in Endocrinology and Metabolism--Vol.
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Examples of pharmacological effects upon a fetus after drugs have been administered to the mother include: masculinisation of the female fetus by androgenic hormones, hypothyroidism in a newborn infant due to propylthiouracil given to the mother for the treatment of hyperthyroidism, intrauterine death or neonatal haemorrhage due to the use of coumarin anticoagulants, prolonged symptomatic hypoglycaemia following the use of chlorpropamide during pregnancy, and early depression of activity with possible later withdrawal symptoms following the use of a host of tranquillisers, sedatives, and narcotic analgesics. There is great variability in the absorption of drugs by a newborn infant when administered other than by the parenteral route and this route is therefore preferable for systemic therapy. Even with parenteral administration various physiological and anatomical factors govern the absorption of a drug. Factors limiting the value of subcutaneous administration for instance are: the volume that can be administered without compromising the blood flow to overlying skin; the possibility of causing damage to adjacent tissues due to the concentrated or caustic nature of the injected material; and variation in absorption due to poor circulation to peripheral areas. The latter is especially important in sick neonates and in very immature infants whose poor peripheral circulation is compromised further by hypothermia. The skin of the newborn infant is marked by immaturity of the stratum corneum (Solomon and Esterly, 1971) which allows the absorption of topical preparations to a far greater degree than occurs under usual circumstances in more mature patients. There are also potential drawbacks to the use of repeated intramuscular injections in newborn infants such as poor peripheral circulation in sick infants, the number of injections that can be given safely into the small muscle mass of the infant, and the amount of material that can be given in each dose. In spite of these disadvantages, however, the intramuscular route is usually both safe and adequate to provide enough drug in the circulation for the treatment of disease. When a drug is injected intravenously, it bypasses all of the factors that affect absorption and enters the circulation directly. Certain parenteral preparations can lead to untoward effects when given intravenously, however, due to the physical and chemical properties of the active agent as well as the buffers, preservatives and other additives in the preparation. Thus, the use of highly concentrated solutions or those with sclerosing properties can lead to thrombophlebitis or sloughing of tissues from infiltration around the site of injection. The intravenous administration of paraldehyde may lead to acute pulmonary difficulty due to the aggregation of droplets of this waterinsoluble agent within pulmonary blood vessels. The aminoglycoside antibiotics (e.g. kanamycin and streptomycin) may interfere with breathing when administered in high doses intravenously because they have a curariform action at high blood concentrations (Weinstein, 1970). Injection of drugs via umbilical vessel catheters may either cause serious liver damage (umbilical vein) or marked renal or extremity ischaemia (umbilical artery) (Symansky and Fox, 1972). When appropriate precautions are taken, however, the intravenous route is safe for the treatment of seriously ill infants.
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DISTRIBUTION
Drugs which are used clinically are able to pass through body membranes. Thus, for practical purposes, no drug is limited to the intravascular compartment after it has been absorbed. Distribution is the process that leads to the partition of drugs between the various body organs and tissues. The exact distribution of a drug at a given time after a dose depends upon physiological conditions within the patient and the physicochemical properties of the drug itself. For most drugs, if measurements of tissue concentrations are made soon after they are administered, the distribution is found to be almost directly related to the blood flow to the individual organ or tissue (Schanker, 1971). However, the final distribution of a drug (and its concentration in various tissues) is governed by such factors as: the pH of the patient's body fluids, the patient's size and weight, the proportion of the total body water that is intracellular, the drug's lipid solubility, its ionisation constant and the extent to which it is bound to plasma, or to other body proteins (Weber and Cohen, 1975). Thus, final distribution and sites of highest concentration must be determined experimentally. The relationship of plasma protein binding to safe drug therapy is especially important in the newborn infant. Drugs that are absorbed into the circulation are bound to varying degrees to the plasma proteins, especially to albumin. The bound component of a drug is neither pharmacologically active nor readily diffusable. Thus, the molecules that are bound to albumin represent an internal reservoir of the drug. Alterations in the plasma albumin concentration can have a profound effect upon the size of this potential reservoir and upon the concentration of the drug in various tissues. Thus, the relative hypoalbuminaemia of immaturity must be taken into account when suggesting therapeutic regimens for premature infants, or toxic drug concentrations might build up in their tissues due to the small size of their plasma reservoir compartment. When several drugs compete for protein binding sites, the distribution of one or more of them may be altered. The distribution of bilirubin can also be altered when a drug interferes with its protein binding. This drug--bilirubin interaction represents a unique hazard for neonatal patients and is an example of the effect of distribution upon the action of a compound. Premature infants treated with sulfisoxazole (sulphafurazole) develop kernicterus when their serum bilirubin concentrations are well below the usual dangerous range (Silverman et al, 1956). Kernicterus occurs in those infants because bilirubin, displaced from plasma binding sites by the sulphonamide, gains access to the brain where it has a cytotoxie effect (Odell, 1959). METABOLISM
Many antibiotic agents are sufficiently water-soluble at physiological pH to be excreted in the urine in an unchanged form. For example, the various penicillins and the aminoglycoside agents (kanamycin, gentamicin, etc.) can be recovered almost quantitatively in the urine in active form after administration to patients at all stages of development. However, most pharmacological agents are highly lipid-soluble chemical compounds that are
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reabsorbed in the renal tubules after glomerular filtration. Thus, their elimination from the body is greatly impeded and they would persist in high concentration for long periods of time if no other mechanism were available to assist their excretion (Brodie, 1964). These agents are altered within the body by a series of enzymatic drug-metabolising reactions. There are two major categories of drug metabolising reactions: Phase I or non-synthetic reactions (oxidations, reductions, and hydrolyses); and Phase II or synthetic reactions (conjugations). The enzymes that catalyse drug metabolism may be found in vitro in several body tissues, but most drug metabolism in vivo appears to be carried out in the liver.
Non-synthetic Reactions Phase I or non-synthetic reactions consist primarily of oxidations which are carried out by so-called 'mixed function' oxidases that are fixed to the membranes of the microsomes of the endoplasmic reticulum. The various oxidative reactions that drugs undergo in the body involve the transfer of an 'activated' oxygen atom from its carrier protein to the drug molecule (Table 1). These reactions are catalysed by 'terminal' oxidases, which may or may not be identical with the carrier molecule, cytochrome P-450. However, they all depend upon the activity of the electron transport system that generates the P-450-activated oxygen complex. This electron transport system has been found in microsomes from liver as well as from adrenal cortex where it is required to provide activated oxygen for the hydroxylation steps that take place in steroid biogenesis. The P-450 system and the mixed function oxidases have been discussed extensively elsewhere (Gillette et al, 1969; Estabrook, Gillette and Leibman, 1973). Table 1. Phase I drug oxidation and reduction reactions Oxidations
1. 2. 3. 4. 5. 6. 7. 8.
Hydroxylation of aromatic compounds Hydroxylation of alkyl hydrocarbon chains Deamination O-Dealkylation N-Dealkylation N-Oxidation Sulphoxidation Sulphur--oxygen exchange
Reductions
1. Azo-reduction 2. Nitro-reduction
The products of P-450-associated oxidation and of reduction (Table 1) may be pharmacologically less active, equally active, or more active when compared to the parent compound. Furthermore, while the molecules of these products are generally more polar than the original drug, many must undergo conjugation before they are so polar that complete detoxification and speedy elimination from the body are assured.
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Synthetic Reactions The Phase II or synthetic reactions generally result in the conversion of relatively non-polar molecules into highly polar compounds that can be excreted in either the bile or the urine. Table 2 contains a partial list of the synthetic reactions that are important in drug metabolism in man. Many of these are carried out by enzymes that are fixed to the smooth microsomes or to the mitochondria, but others are catalysed by enzymes that are found in solution within the cell's cytoplasm.
Table 2. Phase
H drug metabolism reactions
Acetylation Ethereal sulphate synthesis Glucuronide conjugation Glycine conjugation Mercapturic acid formation Methylation Thiocyanate formation Synthetic reactions generally involve the transfer of a polar moiety from an 'activated' donor molecule to the drug itself or to the metabolite formed in a primary (oxidative or reductive) enzymatic conversion. Thus, glucuronide conjugates of the drugs are formed when glucuronyl moieties are transferred from uridinediphosphateglucuronic acid (UDP glucuronic acid) to the drug (or its metabolite), and acetylated derivatives are formed by the transfer of an acetyl group from acetyl coenzyme A to the drug. The mechanisms of action of the various enzymes that catalyse the synthetic reactions may be quite complex (Cleland, 1967) and may have initial rate equations that contain numerous rate and equilibrium constants (Cleland, 1963). Thus, for example, the enzymatic acetylation of aromatic amine and hydrazine compounds proceeds according to a binary 'ping-pong' mechanism and has kinetic 'constants' that vary as the substrate concentrations are varied systematically (Weber and Cohen, 1967). This kinetic complexity renders studies of the ontogenesis of drug metabolising enzymes very difficult to carry out and to interpret. Another level of complexity is introduced into the study of synthetic reactions by the chemical diversity of the compounds that may be conjugated with the same polar moiety. For example, UDP glucuronic acid, the most versatile of the donors, can interact with enzymes that catalyse the conjugation of at least 16 different chemical groups (Williams, 1959). The number of different conjugating enzymes (transferases) involved in glucuronide conjugation and their specificity for the various chemical groups of receptor molecules are unknown.
Development of Drug Metabolising Capacity Fetus PHASEI. The human fetus is capable of carrying out a number of the oxidative reactions that are associated with drug metabolism at an early stage of intra-
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uterine development. It is difficult to interpret some of the studies quantitatively, however, since whole cells which may contain most of the Phase I activity are present in 'homogenates' of very early fetal liver (Ackermann, Rane and Ericsson, 1972) and the early studies did not include an examination of the low speed centrifugal pellets for activity. Various investigators have found that a number of compounds are oxidised by liver preparations from 12 to 16-week-gestation human fetuses. These compounds include: aminopyrine (amidopyrine) (Yaffe et al, 1970), aniline, and ethylmorphine (Rane and Ackerman, 1972), benzpyrene (Pelkonen et al, 1971a), chlorpromazine (Pelkonen et al, 1971b), desmethylimipramine (desipramine) (Rane et al, 1973), and hexabarbital (hexobarbitone) (Pelkonen, Vorne and K~irki, 1969). Indeed, it has been suggested that some fetuses may metabolise certain drugs more rapidly than some adults. This has led to speculation concerning the possibility that fetal drug metabolism may yield more of a specific metabolite than is produced by the pregnant woman herself (Pelkonen et al, 1973). The fact that a human fetus is capable of carrying out oxidative drug metabolism at an early stage of development has led to concern over the possible side-effects of the metabolites produced early in the second trimester. Thus epoxides, which are potential toxins and teratogens, are produced by fetal hepatic enzyme systems as early as the twelfth week of gestation (Rane and Gustafsson, 1973). The actual effect of such compounds upon fetal development is yet to be determined. Aromatic nitro-group reduction has been detected in human fetal liver homogenates, with p-nitrobenzoic acid as the 'drug' substrate, as early as seven weeks of gestation (Juchau, 1971). PHASE II. Little is known about the early development of synthetic processes in the human fetus, but one report indicates that liver preparations from 19 to 21-week human fetuses failed to catalyse the formation of the glucuronide conjugates of p-nitrophenol, 1-naphthol and 4-methylumbelliferone in vitro (Rane, Sj~qvist, and Orrenius, 1973). Newborn infant Most of the pharmacological studies carried out in human infants to date have been concerned with drugs such as antibiotics which are excreted unchanged in the urine. Thus, they have been mainly pharmacokinetic studies; evaluations of drug metabolism early in extrauterine life have not been carried out extensively. The advent of newer techniques for drug (and drug metabolite) analysis which require only small amounts of blood, however, now makes it possible to study more drugs more completely in neonatal patients. PHASEI. Nortryptyline hydroxylation can be catalysed in the newborn infant. One infant whose mother had taken a large overdose was found to be excreting the hydroxylated metabolite soon after birth (Sj~Sqvist et al, 1972). However, the serum half-life of the drug in this infant was still prolonged. Diphenylhydantoin hydroxylation may be carried out quite efficiently soon after birth according to studies in infants who had been exposed to the drug throughout gestation (Mirkin, 1971; Reynolds and Mirkin, 1973; Rane et al,
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1974). Other studies, carried out after a single dose to infants who had been unmedicated in utero, indicate that the metabolism noted was the result of normal neonatal hepatic function and not due to enzyme induction by the drug acquired transplacentally (Jailing et al, 1970). Hydroxylation of diazepam to form oxazepam proceeds very slowly in the newborn infant (Mandelli et al, 1975). Oxidative N-demethylation of diazepam is carried out more rapidly than hydroxylation. These data were derived from infants who acquired the drug transplacentally following either single or repeated doses to the pregnant woman at term. The metabolite, N-demethyldiazepam, retains much of the pharmacological activity of the parent compound and is excreted quite slowly by the newborn infant (Mandelli et al, 1975). The oxidative metabolism of a number of other drugs has been studied in newborn infants. These drugs include acetanalide (Vest and Streiff, 1959), tolbutamide (Nitowsky, Matz and Berzofsky, 1966), and mepivacaine (Meffin, Long and Thomas, 1973). In all cases the production of the oxidative metabolite appeared to proceed at a much slower rate in the infant than in older children or in adults. PHASE I1. Newborn infants fail to conjugate bilirubin with glucuronide efficiently during the first few days of life. Similarly, there is a failure to form the N-glucuronide of chloramphenicol early in postnatal life and unfortunate results can occur when this development-related difference in metabolic capacity is not considered clinically (Weiss, Glazko and Weston, 1960). Glucuronide conjugates of N-demethyldiazepam and oxazepam, the two main products of Phase I metabolism of diazepam, are formed and excreted more slowly in premature infants than in full-term infants and the latter excrete the glucuronide conjugates of these compounds much less rapidly than do older children (Morselli et al, 1973). Glucuronide and sulphate conjugates of the product of diphenylhydantoin hydroxylation (Phase I) are found in the urine of newborn infants after they receive the drug transplacentally, but they appear to be formed quite slowly in infants when compared to adults (Reynolds and Mirkin, 1973). Both the glucuronide and the glycine conjugates of salicylate are formed quite slowly by newborn infants (Garrettson, Procknal and Levy, 1975). Sulphadiazine is eliminated by premature and full-term infants more slowly than by older infants and children (Fichter and Curtis, 1956). This is probably related to slower conversion of the drug to its conjugated metabolite, N-4-acetyl sulphadiazine. This delayed excretion of drugs that are usually conjugated with an acetyl group prior to elimination has been corroborated recently in several infants who received isoniazid transplacentally (Miceli et al, 1975). The rate of elimination of the antituberculosis agent was so markedly prolonged in these infants that it fell far outside of the usual limits for the genetically determined 'slow acetylator' adults. EXCRETION
Most drugs and drug metabolites are eliminated from the body in the urine. The rate of excretion of drugs in the urine may be limited by the ability of the
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kidney to filter and excrete them. Since drug metabolism proceeds very slowly and renal blood flow, glomerular filtration rate and tubular function are all diminished in newborn infants, the urinary excretion of drugs is generally delayed during the neonatal period. When newborn infants are to be given drugs that are excreted unchanged in the urine, such as the penicillins and the aminoglycoside antibiotics (e.g. streptomycin, kanamycin), the dose must be adjusted for the tendency of these drugs to accumulate within the body. This will minimise the possibility that toxic concentrations will be reached in the patient. Some drugs reach high concentrations in the bile and are eliminated in the faeces. Nafcillin, a semisynthetic penicillin, is eliminated in this way, but still tends to build up in the newborn infant when large doses are administered. This indicates either that biliary excretion is diminished or that enterohepatic recirculation is increased during the neonatal period (O'Connor et al, 1964). COMMENT Some of the doses and regimens recommended for use in newborn infants have been derived from information on the pharmacokinetics of the drugs in newborn infants, while others are recognised to be safe and effective for use in newborns because of empirical observations gathered over many years. These are the only two bases for recommending drug doses for the most immature patients. It is no longer acceptable to use the commonly available formulae related, for instance, to adult weight to derive such doses, since we know now that the effect of a drug in the body is governed by its distribution, metabolism and excretion, rather than by the weight or size of the patient. Physicians who treat newborn infants must resist the temptation to use new drugs in their patients indiscriminately until there are data available to guide them. The constraints placed upon human experimentation by ethical considerations have made the investigation of new drugs for introduction into the pharmacopoeia for neonatal patients especially difficult. If objective pharmacological, therapeutic and toxicological data are to be gathered so that newer agents may be useful for future patients, physicians who have to use such drugs out of therapeutic necessity should endeavour to study as many parameters of drug usage as possible and follow up their patients for as long as possible.
SPECIFIC GROUPS OF DRUGS Antibiotics The penicillins Penicillin G is effective against infections caused by all gram-positive cocci that do not produce penicillinase, most gram-positive bacilli, some gramnegative cocci, and the spirochaetes. It is frequently administered along with an agent that is effective against gram-negative bacilli in the therapy of sepsis neonatorum, especially when the causative organism has not been identified.
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Penicillin G is excreted in the urine, mainly as the biologically active compound. Thus, excretion is the main factor that controls serum levels of penicillin and metabolism can be ignored in determining the appropriate dose. However, the renal clearance of penicillin is markedly diminished in newborn infants (Barnett et al, 1949) and, following small doses of this drug, higher, more sustained blood levels are found in such patients than in older children. Six hours after an intramuscular dose of 22 000 units/kg, the mean serum level in full-term infants is 5.45 units/ml, while in children from 3 to 13 years of age it is only 0.005 units/ml. A daily dose of 50 000 units/kg, administered intramuscularly in divided doses every 12 hours, is sufficient to achieve a therapeutic effect in neonates (Huang and High, 1953). Penicillin is usually administered to newborn infants by the intramuscular route, but when intravenous infusions are used to provide required fluids and electrolytes, the intravenous route may be less traumatic to the patient and should be used. Penicillin may be absorbed quite efficiently from the gastrointestinal tract by some newborn infants (Huang and High, 1953). However, oral administration of penicillin during the neonatal period should be discouraged since reliable absorption should be assured in all infants who require therapy. SEMISYNTHETICPENICILL1NS.Methicillin or oxacillin can be used for the treatment of neonatal infections caused by penicillinase-producing organisms. The former should be avoided in areas where methicillin-resistant staphylococci are common. Cloxacillin and dicloxacillin may displace bilirubin at therapeutic concentrations and should not be used in jaundiced infants (Odell, 1973). Ampicillin, another semisynthetic penicillin, is not effective against penicillinase-producing organisms but has a broader antibacterial spectrum than other penicillins and may be effective against many gramnegative bacilli. Some authors suggest that ampicillin be used instead of penicillin G in the therapy of neonatal sepsis of unknown aetiology (Gotoff and Behrman, 1970). Compared with older children and adults, newborn infants show delay in reaching adequate blood concentrations of the oral penicillins, presumably due to delayed absorption (Cohen et al, 1975). The excretion of all of these drugs and the factors that govern their serum levels are similar to penicillin G (Boe et al, 1967).
The cephalosporins The members of this group of antibiotics bear a strong resemblance to the penicillins in chemical structure, mechanism of action and low potential for toxic reactions. The cephalosporins have a broader spectrum than most penicillins, however, and are effective against gram-negative bacilli and against penicillinase-producing staphylococci. Cephatothin is the most commonly used drug in this group. It is not considered to be the first-choice drug in the treatment of any disease, but its low toxicity and broad spectrum make it a useful drug for the treatment of infections in neonates that are due to Escherichia coli which are resistant to both kanamycin and ampicillin. Since cephalosporins are excreted in the same manner as the penicillins, low doses can be used to produce prolonged therapeutic serum levels (Sheng,
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Huang and Promadhattavedi, 1964). Staphylococci that produce penicillinase may adapt to the presence of cephalosporins by producing a cephalosporinase. Thus, the cephalosporins should not be relied upon in the prolonged treatment of serious illness due to penicillin-resistant staphylococci.
The aminoglycosides This group includes kanamycin, gentamicin, streptomycin and neomycin. They are all potent antibacterial drugs that must be given parenterally when used for the treatment of systemic disease because they are not absorbed from the gastrointestinal tract. Kanamycin is effective against many of the gram-negative organisms that are commonly pathogenic in the newborn infant. It is less toxic in the newborn infant than other drugs that have a similar antibacterial spectrum and in conjunction with penicillin is the combination of choice for the treatment of sepsis of unknown aetiology in this age group. It may be used to eliminate enteropathogenic strains of E. coli from the gastrointestinal tract and should be administered orally when used for this purpose. Gentamicin has an even broader antibacterial spectrum than kanamycin and is especially useful for the treatment of infections due to 'resistant' pseudomonas. It should be reserved for the treatment of pseudomonas infections or diseases caused by other gram-negative organisms that are resistant to kanamycin and ampicillin. Streptomycin has no intrinsic advantage over kanamycin, is more toxic than this widely used drug and is not recommended for the treatment of sepsis neonatorum. However, streptomycin is still used to treat congenital tuberculosis, especially in combination with isoniazid. Neomycin, once the drug of choice for the treatment of diarrhoea caused by the enteropathogenic strains of E. coli and for the eradication of these organisms from asymptomatic carriers, is no longer preferred because of the emergence of many resistant strains. It should be administered only via the oral route (when it is used) because of its potential to produce serious toxicity when it is given parenterally. The serum half-life of kanamycin is 8.9 hours in premature infants, and two hours in adults (Axline and Simon, 1964). This prolongation of half-life is due to the fact that the aminoglycosides are excreted in the urine by filtration and immature infants have a diminished glomerular filtration rate. Therapeutically effective serum concentrations of kanamycin (15 to 25 /~g/ml) may be produced and maintained in some newborn infants, without the production of significant toxicity, by the intramuscular administration of 7.5 mg/kg every 12 hours, but newer data indicate that 10 mg/kg may be more appropriate for some patients (Howard and McCracken, 1975). The aminoglycosides may be toxic to the eighth cranial nerve, leading to vertigo or deafness, or toxic to the kidney, leading to proteinuria and azotaemia. Ototoxicity does not appear to occur in immature infants who are treated with the recommended doses of kanamycin for up to 14 days (Eichenwald, 1966). Proteinuria, cylindruria and mild azotaemia may occur in some infants after the first few days of kanamycin therapy and the
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administration of the drug should be stopped if they appear. There is no evidence that permanent renal damage results if the nephrotoxic effects are discovered early and the drug is discontinued promptly.
The polymixins Colistin (polymixin E) is the only member of this group of antibiotics recommended for use in newborn infants. Its use should be limited to the treatment of infections caused by organisms resistant to other antibiotics, since it has a narrow margin of safety. It is sometimes given orally to eradicate enteropathogenic E. coli, but it is not the drug of choice for this purpose. Colistin is excreted unchanged in the urine but, in contrast to other antibiotics, its serum half-life in the newborn does not differ significantly from its half-life in adults (Axline, Yaffe and Simon, 1967). The basis for this apparent paradox has not been explained as yet. A dose as low as 1.5 m g / k g / d a y administered in divided doses intramuscularly every 12 hours has been found to be effective for the treatment of infections in newborn infants. However, the drug is nephrotoxic and urinalyses and tests for azotaemia must be performed every few days during therapy. In all cases, the course of therapy with colistin should not exceed seven to eight days.
Isoniazid This is the most widely used tuberculostatic agent. It has been recommended for the treatment of overt disease, for the treatment of asymptomatic tuberculin reactors and even for prophylaxis in infants who are likely to be exposed repeatedly to persons with active tuberculosis (Avery and Wolfsdorf, 1968). Isoniazid is recommended as one drug in the combination of choice for the treatment of overt congenital tuberculosis and should be part of any therapeutic regimen for tuberculosis in the neonatal period. No serious toxic reactions have been reported to occur in newborn infants after isoniazid administration, but since this drug is not metabolised rapidly by newborn infants, it cannot be excreted efficiently, and blood levels may tend to build up to a dangerous degree in some infants (Cohen and Weber, 1969; Miceli et al, 1975). Thus, its safety in the newborn infant has not been established firmly enough to recommend that it be administered prophylactically during the first month of life.
Cardiac Glycosides Congestive heart failure and paroxysmal supraventricular tachycardia are currently the only two indications for the use of digitalis preparations in newborn infants. Current concepts of the pathophysiology of respiratory distress syndrome and hydrops fetalis indicate that there is no rational basis for the administration of digitalis glycosides in these conditions. Digoxin is the digitalis glycoside of choice for the treatment of neonates. This is because it is absorbed well, acts rapidly and is excreted in a relatively short time. Thus, a therapeutic regimen can be planned rigorously, rapid
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results can be expected once therapy is begun, and any toxic effects that occur during therapy will diminish rapidly when the dose is readjusted. Digoxin is e!iminated from the body in the urine in the active form. There may be a delay in the excretion of the drug after it is administered to newborn infants due to their hepatic and renal immaturity (Soyka, 1972). Furthermore, there may be increased myocardial sensitivity to the effects of digitalis glycosides in the newborn period. The recommended dose of digoxin for newborn infants is therefore slightly lower than that in older infants (Rutkowski, Cohen and Doyle, 1973). Anticonvuisants and Sedatives
Phenobarbital (phenobarbitone) is the most commonly used member of this group of drugs for treating newborn infants. The indications for its use include seizures and neonatal drug withdrawal symptoms. Seizures due to hypoglycaemia or other metabolic derangements should be treated by correcting the underlying metabolic abnormality. Phenobarbital is very effective in reducing or stopping the irritability that is characteristic of infants of narcoticaddicted mothers. In some centres, phenobarbital is administered to prevent the development of hyperbilirubinaemia or to treat those infants who are already jaundiced (Maurer et al, 1968; Trolle, 1968). The action of phenobarbital in this situation depends upon its ability to induce the activity of the enzyme that catalyses the conjugation of bilirubin with glucuronic acid in the liver (Stern et al, 1970). However, since this drug acts to increase the activity of many enzymes in th/e~body, it may have widespread effects that have not been defined to date. Therefore, it should not be used freely during the neonatal period in the absence of seizures or of a history of maternal addiction. Chlorpromazine can be administered instead of phenobarbital to alleviate the symptoms of neonatal narcotic withdrawal. It is not an anticonvulsant, however, and should not be prescribed for the treatment of convulsant seizures. Diazepam (injectable Valium) has been recommended as an anticonvulsant (Rose and Lombroso, 1970) and for the management of neonatal drug withdrawal (Nathenson, Golden and Litt, 1971). However, it has not been shown to be clearly superior to phenobarbital or paraldehyde for treating seizures during the newborn period and is probably no more effective in controlling withdrawal symptoms than phenobarbital or chlorpromazine. Furthermore, it contains a substantial amount of benzoate, an ion that is known to displace bilirubin from its binding sites on albumin (Cohen and Fern, 1972). A recent report indicates that this effect may not be significant clinically (Nathenson, Cohen and McNamara, 1975). Further investigations should be carried out to evaluate whether parenteral diazepam may predispose certain infants to bilirubin encephalopathy before it is used widely to treat infants during the first week of life. Paregoric, camphorated tincture of opium, has been used widely in the past to treat drug withdrawal in the newborn period, but should be eliminated from our list of therapeutic agents since the camphor in it is
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potentially dangerous and has no therapeutic value. Tincture of opium, diluted to yield 0.4 per cent opium, should be used in its place (Neumann and Cohen, 1975). Opiates should not be used in the treatment of diarrhoea in young inf~/nts, however, since they do not suppress fluid losses in such an instance and may only mask the severity of these losses. Diuretics The indications for diuretic therapy during the neonatal period include congestive heart failure and suspected acute renal failure. In the first instance, diuretics are used as adjuncts to digoxin therapy and in the second, as part of a therapeutic trial to determine whether fluid intake should be restricted or not. Ethacrynic acid and furosemide (frusemide) act mainly upon the reabsorption of sodium in the loop of Henle. Their action is not as dependent upon the glomerular filtration rate as is that of mercurial diuretics and they may act very rapidly, even during the neonatal period. However, both of these drugs can inhibit the binding of small molecules by albumin and are therefore potentially hazardous if given to jaundiced infants during the first few weeks of life (Sellers and Koch-Weser, 1971; Shankaran and Poland, 1975). The thiazide diuretics should not be used to treat infants during the first week of life, since they are inefficient in the presence of diminished glomerular filtration rate and may displace bilirubin from its albumin binding sites (Cohen and Ganapathy, 1973). Furthermore, they are photosensitising agents and might cause adverse reactions among infants who are treated with phototherapy. It is also possible that their carbonic anhydrase inhibiting activity can prolong the period of recovery from birth asphyxia, especially in very small premature infants. In the event that a therapeutic trial with a diuretic agent is indicated to define the state of an infant's renal function, an osmotic agent such as mannitol should be the first choice during the first week of life. Thereafter, one of the potent agents mentioned above (ethacrynic acid or furosemide) should probably be used. CONCLUSION Although the use of drugs to treat the most immature patients safely is less of a problem to paediatricians today than ever before, developmental pharmacology has not yet reached a stage where clinicians can depend routinely upon the safety for newborn infants of new therapeutic agents that are introduced into general clinical use. There will have to be a great increase in our knowledge of neonatal physiology and of the interaction of drugs with the infant's physiological systems before new drugs can be introduced with rational recommendations for use in the neonatal field. The drugs mentioned in this chapter will provide for most clinical situations so that there will be little need to use newer drugs in infants before appropriate studies have been completed.
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REFERENCES Ackermann, E., Rane, A. & Ericsson, J. L. E. (1972) The liver microsomal monooxygenase system in the human fetus: distribution in different centrifugal fractions. Clinical Pharmacology and Therapeutics, 13, 652-662. Asling, J. & Way, E. L. (1971) Placental transfer of drugs. In Fundamentals of Drug Metabolism and Drug Disposition (Ed.) La Du, B. N., Mandel, H. G. & Way, E. L. Baltimore: Williams and Wilkins. Avery, M. E. & Wolfsdorf, J. (1968) Diagnosis and treatment: Approaches to newborn infants of tuberculous mothers. Pediatrics, 42, 519. Axline, S. G. & Simon, H. J. (1964) Clinical pharmacology of antimicrobials in premature infants: I. Kanamycin, streptomycin and neomycin. In Antimicrobial Agents and Chemotherapy, p. 135. Ann Arbor: American Society for Microbiology. Axline, S. G., Yaffe, S. J. & Simon, H. J. (1967) Clinical pharmacology of antimicrobials in premature infants: II. Ampicillin, methicillin, oxacillin, neomycin, and colistin. Pediatrics, 39, 97. Barnett, H. L., McNamara, H., Shultz, S. & Tompsett, R. (1949) Renal clearances of sodium penicillin G, procaine penicillin G, and inulin in infants and children. Pediatrics, 3, 418. Boe, R. W., Williams, C. P., Bennett, J. V. & Oliver, T. K. (1967) Serum levels of methicillin and ampicillin in newborn and premature infants in relation to postnatal age. Pediatrics, 39, 194. Brodie, B. B. (1964) Of mice, microsomes and man. Pharmacologist, 6, 12. Cleland, W. W. (1963) The kinetics of enzyme-catalyzed reactions with two or more substrates or products. I. Nomenclature and rate equations. Biochimiea et Biophysiea Acta, 67, 104-137. Cleland, W. W. (1967) Enzyme kinetics. Annual Review of Biochemistry, 36, 77-112. Cohen, M. D., Raeburn, J. A., Devine, J., Kirkwood, J., Elliot, B., Cockburn, F. & Forfar, J. O. (1975) Pharmacology of some oral penicillins in the newborn. Archives of Disease in Childhood, 50, 230. Cohen, S. N. & Fern, L. M. (1972) The displacement of albumin-bound bilirubin by benzoate: A hazard of the use of diazepam in newborn infants. Pediatric Research, 6, 144. Cohen, S. N. & Ganapathy, S. K. (1973) Unpublished observations. Cohen, S. N. & Weber, W. W. (1969) Newborn infants of tuberculous mothers - - further comment. Pediatrics, 43, 303 (letter to Editor). Cohen, S. N., Baumgartner, R., Steinberg, M. S. & Weber, W. W. (1973) Changes in the physieochemical characteristics of rabbit liver N-acetyl-transferase during postnatal development. Biochimica et Biophysica Acta, 304, 473-481. Eichenwald, H. F. (1966) Some observations on dosage and toxicity of kanamycin in premature and full term infants. Annals of the New York Academy of Sciences, 132, 984. Estabrook, R. W., Gillette, J. R. & Leibman, K. C. (1973) The Second International Symposium on Microsomes and Drug Oxidations. Drug Metabolism and Disposition, 1, 1-486. Fichter, E. G. & Curtis, J. A. (1956) Sulfonamide administration in newborn and premature infants. Pediatrics, 18, 50-58. Garrettson, L. K., Proeknal, J. A. & Levy, G. (1975) Fetal acquisition and neonatal elimination of a large amount of salicylate. Study of a neonate whose mother regularly took therapeutic doses of aspirin during pregnancy. Clinical Pharmacology and Therapeutics, 17, 98-103. Gillette, J. R., Conney, A. H., Cosmides, G. J., Estabrook, R. W., Fouts, J. R. & Mannering, G. J. (1969) Microsomes and Drug Oxidations. New York: Academic Press. Gotoff, S. P. & Behrman, R. E. (1970) Neonatal septicemia. Journal of Pediatrics, 76, 142. Howard, J. B. & MeCraeken, G. H. Jr (1975) Reappraisal of kanamycin usage in neonates. Journal of Pediatrics, 86, 949-956. Huang, N. N. & High, R. H. (1953) Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. Journal o f Pediatrics, 42, 657. Jalling, B., Bor~us, L.-O., Rane, A. & Sj6qvist, F. (1970) Plasma concentrations of diphenylhydantoin in young infants. Pharrnacologia Clinica, 2, 200-202.
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Juchau, M. R. (1971) Drug biotransformation in the human fetus. Nitro group reduction. Archives Internationales de Pharmacodynamie et de Thdrap&, 194, 346-358. Mandelli, M., Morselli, P. L., Nordio, S., Pardi, G., Principi, N., Sereni, F. & Tognoni, G. (1975) Placental transfer of diazepam and its disposition in the newborn. Clinical Pharmacology and Therapeutics, 17, 564-572. Maurer, H. M., Wolff, J. A., Finster, M., Poppers, P. J., Pantuck, E., Kuntzman, R. & Conney, A. H. (1968) Reduction in concentration of total serum bilirubin in offspring of women treated with phenobarbital during pregnancy. Lancet, if, 122. Meffin, P., Long, G. J. & Thomas, J. (1973) Clearance and metabolism of mepivacaine in the human neonate. Clinical Pharmacology and Therapeutics, 14, 218-225. Miceli, J., Olson, W., Weber, W. W. & Cohen, S. N. (1975) Unpublished observations. Mirkin, B. L. (1971) Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism and possible teratogenic effects. Journal of Pediatrics, 78, 329-337. Mitani, F., Alvares, A. P., Sassa, S. & Kappas, A. (1971) Preparation and properties of a solubilized form of cytochrome P-450 from chick embryo liver microsomes. Molecular Pharmacology, 7, 280-292. Morselli, P. L., Principi, N., Tognoni, G., Reali, E., Belvedere, G., Standen, S. M. & Sereni, F. (1973) Diazepam elimination in premature and fullterm infants and children. Journal of Perinatal Medicine, 1, 133-141. Nathenson, G., Cohen, M. I. & McNamara, H. (1975) The effect of Na benzoate on serum bilirubin of the Gunn rat. Journal of Pediatrics, 86, 799-803. Nathenson, G., Golden, G. S. & Litt, I. F. (1971) Diazepam in the management of the neonatal narcotic withdrawal syndrome. Pediatrics, 48~ 523. Neumann, L. L. & Cohen, S. N. (1975) The neonatal narcotic withdrawal syndrome. A therapeutic challenge. Clinics in Perinatology, 2, 99-109. Nitowsky, H. M., Matz, L. & Berzofsky, J. A. (1966) Studies on oxidative drug metabolism in the fullterm newborn infant. Journal of Pediatrics, 69, 1139-1149. O'Connor, W. J., Warren, G. H., Mandala, P. S., Edrada, L. S. & Rosenman, S. B. (1964) Serum concentrations of nafcillin in newborn infants and children. In Antimicrobial Agents and Chemotherapy, p. 188. Ann Arbor: American Society for Microbiology. Odell, G. B. (1959) The dissociation of bilirubin from albumin and its clinical implications. Journal of Pediatrics, 55, 268. Odell, G. B. (1973) Personal communication. Pelkonen, O., Vorne, M. & K~trki, N. T. (1969) Drug-metabolizing activity in the liver, intestine and kidney of human foetus. Acta Physiologica Scandinavica, 77 (Supplement), 330-369. Pelkonen, 0., Vorue, M., Arvela, P., Jouppila, P. & K~irki, N. T. (1971a) Drug metabolizing enzymes in human fetal liver and placenta in early pregnancy. Scandinavian Journal of Clinical and Laboratory Investigation, 27 (Supplement 116), 7. Pelkonen, O., Vorue, M., Jouppila, P. & K/irki, N. T. (1971b) Metabolism of chlorpromazine and p-nitrobenzoie acid in the liver, intestine, and kidney of the human foetus. Acta Pharmacologica et Toxicologiea, 29, 284-294. Pelkonen, O., Kaltiala, E. H., Larmi, T. K. I. & Kiirki, N. T. (1973) Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clinical Pharmacology and Therapeutics, 14, 840-846. Rane, A. & Ackermann, E. (1972) Metabolism of cthylmorphine and aniline in human fetal liver. Clinical Pharmacology and Therapeutics, 13, 663-670. Rane, A. & Gustafsson, J. A. (1973) Formation of a 16,17-transglycolic metabolite from a 16-dehydro-androgen in human fetal liver mierosome. Clinical Pharmacology and Therapeutics, 14, 833-839. Rane, A., Sj6qvist, F. & Orrenius, S. (1973) Drugs and fetal metabolism. ClinicalPharmacology and Therapeutics, 14, 666-672. Rane, A., Garle, M., Borga, O. & Sj~qvist, F. (1974) Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clinical Pharmacology and Therapeutics, 15, 39-45. Rane, A., von Bahr, C., Orrenius, S. & Sj6qvist, F. (1973) Drug metabolism in the human fetus. In InternationalSymposium on FetalPharmacology (Ed.) Bor6us, L. O. pp. 287-303. New York: Raven Press.
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Reynolds, J. W. & Mirkin, B. L. (1973) Urinary corticosteroid and diphenylhydantoin metabolite patterns in neonates exposed to anticonvulsant drugs in utero. Clinical Pharmacology and Therapeutics, 14, 891-897. Rose, A. L. & Lombroso, C. T. (1970) Pathological and electroencephalographic features in 137 full term babies with a long term follow-up. Pediatrics, 45, 404. Rutowski, M. M., Cohen, S. N. & Doyle, E. F. (1973) Drug therapy of heart disease in pediatric patients. If. The treatment of congestive heart failure in infants and children with digitalis preparations. American Heart Journal, 86, 270-275. Schanker, L. S. (1971) Drug absorption. In Fundamentals of Drug Metabolism and Drug Disposition (Ed.) La Du, B. N., Mandel, H. G. & Way, E. L. Baltimore: Williams and Wilkins. Sellers, E. M. & Koch-Weser, J. (1971) Kinetics and clinical importance of displacement of warfarin from albumin by acidic drugs. Annals of the New York Academy of Sciences, 179, 213. Shankaran, S. 8/Poland, R. L. (1975) The displacement of bilirubin from albumin by furosemide. Pediatric Research, 9, 370. Sheng, K. T., Huang, N. N. & Promadhattavedi, V. (1964) Serum concentration of cephalothin in infants and children and the placental transmission of the antibiotic. In Antimicrobial Agents and Chemotherapy, p. 200. Ann Arbor: American Society for Microbiology. Silverman, W. A., Andersen, D , H., Blanc, W. A. & Crozier, D. N. (1956) Difference in mortality rate and incidence of kernicterus among premature infants alloted to two prophylactic antibacterial regimens. Pediatrics, 18, 614. Sj~qvist, F., Bergfors, P. G., Borga, O., Lind, M. & Ygge, H. (1972) Plasma disappearance of nortriptyline in a newborn infant following placental transfer from an intoxicated mother: Evidence for drug metabolism. Journal of Pediatrics, 80, 496-500. Solomon, L. M. & Esterly, N. B. (1971) Neonatal dermatology. I. The newborn skin. Journal of Pediatrics, 77, 888. Soyka, L. F. (1970) Isolation and characterization of reduced nicotinamide adenine dinucleotide phosphate: ferricytochrome c oxidoreductase and identification of cytochrome b5 in the liver of human infants. Biochemical Pharmacology, 19, 945-951. Soyka, L. F. (1972) Clinical pharmacology of digoxin. Pediatric Clinics of North America, 19, 240. Stern, L., Khanna, N. N., Levy, G. & Yaffe, S. J. (1970) Effect of phenobarbital on hyperbilirubinemia and glucuronide formation in newborns. American Journal of Diseases of Children, 120, 26. Symansky, M. R. & Fox, H. A. (1972) Umbilical vessel catheterization: Indications, management and evaluation of the technique. Journal of Pediatrics, 80, 820. Trolle, D. (1968) Decrease of total serum bilirubin concentration in newborn infants after phenobarbital treatment. Lancet, if, 705. Vest, M. F. & Streiff, R. R. (1959) Studies on glucuronide formation in newborn infants and older children. American Journal of Diseases of Children, 98, 688-693. Weber, W. W. & Cohen, S. N. (1967) N-acetylation of drugs: isolation and properties of an N-acetyltransferase from rabbit liver. Molecular Pharmacology, 3, 266-273. Weber, W. W. & Cohen, S. N. (1975) Aging effects and drugs in man. In Handbook of ExperimentalPharmacology, Vol. XXVIII/3. (Ed.) Eichler, O., Farah, A., Herken, H. & Erich, A. D. New York: Springer Verlag. Weinstein, L. (1970) The Pharmacological Basis of Therapeutics (Ed.) Goodman, L. S. & Gilman, A. 4th edition, p. 1287. New York: Macmillan. Weiss, C. F., Glazko, A. J. & Weston, J. K. (1960) Ct'doramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in excessive doses. New England Journal of Medicine, 262, 787-794. Williams, R. T. (1959) Detoxication Mechanisms, 2nd edition. New York: John Wiley. Yaffe, S. J. (1972) Pediatric pharmacology. Pediatric Clinics of North America, 19, 1-256. Yaffe, S. J., Rane, A., Sj6qvist, F., Bor6us, L. O. & Orrenius, S. (1970) The presence of a monocygenase system in human fetal liver microsomes. Life Sciences, 9, 1189-1200.