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Minimising potential side-effects of medication at different ages

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Jennifer Kelly, BA (Hons), MSc, RN, DipN, DipEd.

Senior Lecturer, Homerton College, Cambridge

This article, and the article on antibiotic resistance published in the September 2001 issue, has been adapted from Jennifer Kelly's book Adverse Drug Effects: A nursing concern (2000), published by Whurr Publishers, London

This article, and the article on antibiotic resistance published in the September 2001 issue, has been adapted from Jennifer Kelly's book Adverse Drug Effects: A nursing concern (2000), published by Whurr Publishers, London

Until the thalidomide disaster, the placenta was believed to constitute a barrier to environmental teratogens (agents that cause birth defects). It is now recognised that lipid-soluble drugs can preferentially cross the placenta, as can a large number of lipid-insoluble drugs. As a result, drugs intended to treat the mother may cross the placenta and exert harmful effects on the developing fetus. Those drugs most easily transported across the placenta include steroids, narcotics, anaesthetics and some antibiotics.

Drugs may have harmful effects on the foetus at any stage during pregnancy, although the risks are greatest during the first trimester. Drugs taken during this period may produce congenital malformation; for example, high-dose glucocorticoids may cause cleft palate. During the second and third trimesters, drugs may still have adverse effects by affecting the growth and functional development of the fetus or through toxic effects on fetal tissue. Drugs given shortly before term or during labour may have adverse effects on labour or on the neonate after delivery. For example, aspirin may cause premature closure of the ductus arteriosus in the later part of pregnancy and may reduce platelet aggregation, so increasing the risk of intracranial haemorrhage in premature and low-birthweight infants (Ruggiero, 1992). This explains why paracetamol-containing analgesics are preferable to aspirin during pregnancy.

Drugs should be prescribed in pregnancy only if the expected benefit to the mother is greater than the risk to the fetus. The case of epilepsy poses a dilemma because anti-epileptic drugs may cause fetal hydantoin syndrome, which results in craniofacial, limb and heart defects (McManus Kuller, 1990). However, withholding medication increases the risk of fits, and a single convulsion may lead to fetal mortality or morbidity from hypoxia or a placental abruption. This dilemma needs to be discussed with the mother so that she is fully informed of the risks and is involved in the decision of choosing how to manage her epilepsy most effectively for herself and her baby. The usual treatment is the lowest effective dose of the favoured anticonvulsant and close monitoring of blood levels of the drug throughout pregnancy.

Breastfeeding
Although most drugs do appear in minute amounts in breast milk, due to the advantages of breastfeeding, only a few drugs are truly contraindicated for breastfeeding mothers. Contraindicated drugs include bromocriptine, cyclophosphamide, cyclosporin and lithium (Banta-Wright, 1997). Instead, it is more useful to consider the factors that influence the passage of drugs into breast milk and to consider strategies to minimise infant exposure to drugs while breastfeeding (Box 1).

Immediately after birth the spaces between the myoepithelial cells of the alveolae of the breast are large and allow the passage of plasma proteins such as IgA, as well as drugs, into breast milk. However, within a week of birth the spaces close, so that only low molecular-weight drugs can pass into the milk. Thus, drugs such as heparin and insulin are normally unable to cross the alveolar membrane. In addition, if drugs are highly protein bound, like phenytoin, they are confined to the plasma compartment and transfer to breast milk only in small amounts. Conversely, highly lipid-soluble drugs such as diazepam transfer easily into breast milk, where they accumulate.

Appendices 4 and 5 of the British National Formulary (BMA/RPSGB, 2001) must be consulted when advising pregnant and lactating women about drugs, as clinical data on drug use in pregnancy is continually changing.

Neonates, infants and children
Children differ from adults in size, in the proportions and constituents of their bodies, and in their physiology. Furthermore, children form a diverse group, and their diversity is increasing as sophisticated technology keeps younger and younger preterm infants alive. It is important to allow for this diversity when prescribing and administering drugs to young people. However, this can be difficult as the pharmacological data, which is generally well described for adults, is sparse for the child because the relevant research has not been undertaken (Gilman and Gal, 1992; Zenk, 1994).

Administration and absorption - Babies and young children cannot swallow tablets, and so require liquid formulations. However, syrups have a high sugar content which can cause dental caries, while powdered drugs used to treat asthma can be so acidic that they cause tooth erosion (O'Sullivan and Curzon, 1998). Dyes such as tartrazine are used in some formulations to promote compliance, but they may cause hyperkinesis in some children. A further problem for neonates is that drugs are not available in suitable concentrations, necessitating complex dilutions, which increases the risk of drug errors (Ramirez, 1989; Skaer, 1991).

Many factors alter the absorption of drugs in children. Most drugs are absorbed in the intestines, but some are absorbed in the stomach. Absorption from the stomach is affected by gastric acidity, which varies according to age (Box 2).

Absorption is affected by common illnesses such as vomiting and diarrhoea, which increase gastric motility and decrease drug absorption. Pancreatic enzyme activity is decreased at birth and the age at which adult levels of activity develop is dependent on the specific enzyme (Niederhauser, 1997). Thus, drugs that rely on enzyme activity to aid absorption may demonstrate variable bioavailability. Reduced levels of bacterial flora increase the bioavailability of drugs such as digoxin, which is normally reduced by intestinal organisms (Wink, 1991).

Another route of drug administration is topically. Children have a thinner stratum corneum than adults, and thus percutaneous absorption is increased 2.7-fold in the newborn and young infant, compared to the adult (Dionne and McManus, 1993). Premature neonates may have greater absorption problems, because the barrier function of the skin is not intact until 21 days. Furthermore, compared to older children, neonates and infants have a larger surface area-to-volume ratio. Consequently, drugs applied topically, including corticosteroids, may be absorbed excessively. The antiseptic hexachlorophane has been known to be absorbed sufficiently to cause neurotoxicity (Smith, 1985), while deafness has resulted from aminoglycoside/polymixin antibacterial sprays on burns (Grahame-Smith and Aronson, 1992). Such agents should be applied sparingly, and only when absolutely necessary. Absorption is further increased by skin diseases and the use of occlusive dressings and nappies.

Distribution - Infants have proportionally less body fat and more water content than adults. Consequently, infants receiving lipid-soluble drugs, such as diazepam, require smaller doses than adults, while water-soluble drugs, such as aminoglycosides, aminophylline, digoxin and frusemide, need to be given in larger doses (Laurence et al, 1997). Neonates and infants are significantly less able to bind drugs to plasma proteins because they have lower concentrations of serum albumin. There is decreased intermolecular attraction between the drug and plasma protein, and there is competition between the drugs and endogenous substances for the binding sites (Guyon, 1989). This is only clinically important when drugs are more than 80-90% bound. For example, phenytoin is normally 90% plasma-protein bound, but is only 70% bound in neonates and, if doses are not adjusted accordingly, there is a high risk of toxic effects (Niederhauser, 1997).

Endogenous chemicals may be displaced by competition with drugs. There is a significant risk of elevation of plasma bilirubin in the neonate following its displacement from protein-binding sites by sulphonamides, vitamin K, X-ray contrast media or indomethacin. Because the blood-brain barrier in the neonate is more permeable than that of the adult, there is a danger that bilirubin will enter the brain, causing kernicterus. The increased permeability of the brain also means that drugs such as phenobarbitone, morphine and chloral hydrate have an enhanced effect.

Metabolism - At birth, enzyme systems are immature, and for 15 days afterwards there is reduced capacity to dispose of drugs. Thereafter, the metabolic capacity of the liver increases rapidly, but at variable rates for the different enzyme systems. In some enzyme systems, there is a period of enhanced drug metabolism, after which the enzymes gradually decrease to adult levels (Kanneh, 1998a). The variability in enzyme activity means there are dangers in making global assumptions about drug-handling ability in children. For example, hepatic oxidative metabolism and the metabolic process of conjugation with glucuronic acid are deficient in the newborn (Laurence et al, 1997). Consequently, incomplete metabolism of drugs such as morphine, benzodiazepines, paracetamol and phenobarbitone slows their renal clearance and extends their duration of action. A drug of particular concern is chloramphenicol. Decreased capacity for glucuronidation means that doses greater than 25 to 50mg/kg per day can cause 'grey baby' syndrome, which may be fatal (McLeod and Evans, 1992).

Excretion - Neonates have poor renal function and do not excrete drugs effectively (Skaer, 1991). Renal blood flow is reduced, the glomerular filtration rate at birth is 30-40% of that of the adult - corrected for body surface (Aronson, 1993) - and tubular reabsorption and secretion are reduced. Consequently, for those drugs that are dependent on renal excretion for termination of activity, such as aminoglycosides, digoxin, penicillins, salicylates, and thiazide diuretics, dosage modifications must be considered for young infants. By age six to nine months, renal function in children is equivalent to that in healthy adults.

Pharmacodynamic factors - Pharmacodynamic differences between children and adults lead to some unexpected outcomes and adverse effects from drug therapy. For example, antihistamines and barbiturates generally sedate adults, but these drugs induce hyperactivity in many children (Kanneh, 1998b). Conversely, amphetamines, which increase motor and behavioural activity in adults, are used to treat hyperactive children, because these drugs appear to increase attention span and decrease disruptive social behaviour.

In paediatrics, some drugs are not used at all due to the potential harm they may cause (Box 3).

Elderly people
Elderly people make up 20% of the population but take 50% of prescribed drugs, using drugs to treat both acute and chronic age-related disorders (Rajaei-Dehkordi and McPherson, 1997). However, the more drugs a person takes, the greater the risk of side-effects and drug interactions. As a result, adverse drug reactions are two to three times more common in elderly people than in other client groups (Grahame-Smith and Aronson, 1992) and account for an estimated 5-31% of elderly hospitalisations (Cunningham et al, 1997; Kemle, 1997).

Administration and absorption - Elderly people may not be able to open child-resistant containers or blister packs (Sexton and Gokani, 1997). Elderly people may have problems swallowing tablets due to a decline in saliva production (xerostomia). Some tablets and capsules, such as ampicillin, codeine compound analgesics and chlormethiazole, may adhere to the oesophageal mucosa where they can dissolve and cause ulceration. It is therefore important that drugs are taken with at least 60ml of fluid and in an upright position (Channer, 1985). If drugs are given as elixirs, elderly people may have problems measuring out the correct dose due to poor eyesight and tremor. Subcutaneous and intramuscular administration also have their problems because decreased tissue perfusion can slow drug absorption. The trans-dermal route has the advantage that it omits the peaks and troughs in serum drug level seen with conventional therapy, and the toxic effects that the peaks can produce. However, transdermal drugs may not be absorbed effectively in elderly people due to age-damaged skin, which has increased keratin and decreased hydration.

Elderly people tend to have a slower rate of absorption of drugs. In the case of oral medication this occurs because there is a decline in gastric acidity, motility and mixing, as well as atrophy of the microvilli and diminished intestinal blood perfusion. Delays in gastric emptying can produce prolonged contact between the drug and the mucosal surfaces, resulting in higher risk of ulceration from direct toxic agents such as non-steroidal anti-inflammatory drugs (NSAIDs) and potassium chloride. Some drugs, such as antacids, antimuscarinics, narcotics, lithium and isoniazid, may further delay gastric emptying and act synergistically with the ageing process to increase this risk. Enteric-coated drugs help to protect the stomach mucosa from toxic drugs. However, they will be effective only if the patient does not take them at the same time as antacids, which are frequently used to self-medicate oesophageal reflux and heartburn.

Distribution - Drug distribution is affected by changes in body composition associated with ageing, particularly the increase in adiposity, which rises from 18% and 36% in youth to 36% and 48% in elderly men and women respectively (Hudson and Boyter, 1997). Consequently, lipid-soluble drugs, such as diazepam, tend to accumulate, leading to toxicity. Anaesthetics are highly fat-soluble drugs, and so are retained in fatty tissue, partially explaining why elderly people can take several days to fully recover from a general anaesthetic. Elderly people also experience a decline in lean body mass which, together with the increase in fat, results in a decrease in total body water. Thus, there is a reduced volume of distribution for water-soluble drugs, such as ethanol, cimetidine, digoxin and lithium, resulting in increased concentration and adverse effects if the dose is not adjusted accordingly. The problem may be exacerbated by the use of diuretics, which are frequently used to treat congestive cardiac failure.

Plasma proteins decrease only slightly with age, but may fall markedly with acute conditions such as pneumonia and myocardial infarction. There are therefore fewer binding sites for protein-bound drugs such as warfarin, and so there is an increase in the proportion of free drug molecules. This problem is exacerbated when the patient uses more than one protein-bound drug, which leads to competition between the drugs for the binding sites. Poor nutritional intake may add to the problem.

Metabolism - Between the ages of 40 and 80 hepatic blood flow decreases by 40%, leading to decreased first-pass metabolism (metabolism of a drug before its entry into the systemic circulation). A decrease in hepatic mass and enzyme activity leads to reduced metabolism of various drugs, including propranolol, paracetamol and nifedipine. As a result, the half-life of these drugs is prolonged, requiring alteration in dosage regimens in order to minimise the development of toxicity.

Not all enzyme systems are equally affected by ageing. There is a greater decline in the P450 cytochrome enzymes, responsible for oxidative metabolism, than in the enzymes responsible for conjugation. Thus drugs metabolised directly by conjugation, such as lorazepam and temazepam, are preferable to those metabolised by the oxidative route, such as diazepam and chlordiazepoxide.

Excretion - Elderly people have reduced kidney function, exacerbated by chronic conditions such as diabetes and hypertension, resulting in reduced renal clearance. The decrease in clearance is particularly problematic with drugs that are excreted in their active state or as active metabolites, and which have a narrow therapeutic index, such as allopurinol, aminoglycosides, chlorpropamide, and digoxin. The usual method of measuring renal function is to measure creatinine clearance. However, because muscles produce serum creatinine, and the decline of lean muscle mass corresponds with reduced renal function, creatinine levels may be normal even with markedly reduced renal function. Thus in elderly people, serum creatinine clearance becomes a less reliable sign of renal function, making it more difficult to predict the patient's ability to excrete drugs effectively.

Pharmacodynamic factors - For reasons not fully understood, elderly people have increased sensitivity to some drugs, independent of pharmacokinetics. One explanation for this is the deterioration of homeostatic mechanisms (Dunbar, 1996) - elderly people have decreased autonomic responses to positional changes and postural hypotension; autonomic mediated changes in bladder and bowel function and impaired thermoregulation. They may also have reduced cognitive function; impaired postural neuromuscular stability; glucose intolerance; and reduced immune response (Planchock and Slay, 1996). Thus falls, urinary retention, and confusion can result from ill-judged drug prescribing.

As well as homeostatic changes, altered drug response can result from an increased sensitivity of drug-binding sites in elderly people. For example, the sodium-potassium pump found in the cardiac cell membrane has increased sensitivity to digoxin, and so digoxin dosage must be monitored care-fully. Other drugs to which elderly people have increased sensitivity are aminophylline, warfarin, diuretics, hypnotics, sedatives, tranquillisers, antidepressants, neuroleptics and opiates. Part of the reason for the increased sensitivity to drugs acting on the central nervous system is the age-related depletion of the neurotransmitters acetylcholine, dopamine, and serotonin (French, 1996). Elderly people also have binding sites with decreased sensitivity, as in the case of beta-adrenoceptors resulting in diminished pharmacological response to beta-blockers and beta-agonists.

Conclusion
By ensuring a good knowledge of the changes in anatomy and physiology throughout life, nurses will have a better understanding of patient medication, and how to ensure the safety of their clients. Common sense and a few simple strategies can also help to minimise adverse effects (Box 4).

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