Special aspects of pediatric and geriatric pharmacology
Prescribing for children
Both the pharmacokinetics and responses to drugs may differ between neonates, infants and
children compared to adults. There are considerable differences between neonates (<1 month),
infants (1 month to 12 months) and children, because many metabolic and physiological
processes are immature at birth and develop rapidly in the first months of life.
Absorption. Slow rates of gastric emptying and intestinal transit may reduce the rate of drug
absorption in neonates, but total absorption may eventually be more complete because of
longer contact with the intestinal mucosa.
Distribution. Neonates and young children have a lower body fat content and higher total
body water compared to adults; this influences the distribution of both lipid- and watersoluble drugs. The newborn have a lower plasma albumin concentration which also has a
lower affinity for drug binding. In addition, the higher plasma concentrations of free fatty
acids and bilirubin compete with drugs for plasma protein binding sites and vice versa.
The overall effect is reduced plasma protein binding, which increases the apparent volume of
distribution of the drug, but also increases the proportion of drug available for metabolism.
Drugs that are strongly bound to albumin should not be used during neonatal jaundice because
the drugs may displace bilirubin (which is mostly in the unconjugated form) from protein
binding sites, and increase the risk of kernicterus.
Metabolism. The liver drug-metabolizing enzyme systems are immature in the neonate, and
first-pass metabolism and hepatic drug clearance are low, especially for substrates of
CYP1A2 and glucuronidation. When the enzyme systems mature, these processes become
more extensive in young children than in adults because the relative liver mass and hepatic
blood flow are higher.
Elimination. Renal function in the neonate and infant is much less developed than in children
or adults. The glomerular filtration rate in the newborn is about 40% of the adult level and
tubular secretory processes are poorly developed.
In neonates, inefficient metabolism and renal clearance mean that lower doses of all drugs are
needed after allowing for body weight. Overall, in children, the larger volume of distribution
and faster hepatic elimination mean that weight-related doses of metabolized drugs need to be
higher in children than in adults. Prescribed doses are most accurately judged by considering
both age and body surface area. Body surface area is a better guide to appropriate drug
dosage than body weight.
Low doses are safe because they are eliminated by conjugation with little oxidation. However,
in overdose the conjugation reactions are saturated and there is increased cytochrome P450mediated oxidation to an unstable quinone-imine metabolite. Early after an overdose, much of
the toxic metabolite is inactivated by a cytoprotective pathway involving glutathione, but as
the available glutathione becomes depleted there is increased covalent binding and cell death.
Age. Neonates, especially premature infants, often lack certain functional drug-metabolizing
systems. The relative inability to conjugate bilirubin with glucuronic acid and the resultant
development of hyperbilirubinemia is a commonly observed example of this deficiency in
biotransformation. Unlike newborn infants, children are often more adept at metabolizing
drugs on a weight basis than are adults. In fact, biotransformation capacity appears to
diminish with age; the elderly may often exhibit retarded rates of drug metabolism.
For dosage determination, „an adult" is usually interpreted to mean an individual 18 years or
older and weighing approximately 70 kg (about 150 Ib).
Children and many underweight, diseased, or elderly patients require a dosage of
pharmacologically active agent that is lower than that suggested for the normal adult. Very
large or obese patients frequently require a higher dose, although with some drugs (e.g.,
gentamicin) the increased dosage increases the risk of toxicity.
Several rules have been proposed for computing the dosage of a drug for children:
1. Clark's rule,
Child's weight (Ib or kg)
x Adult dose = Child's dose
150 Ib or 70 kg
determines the dose suitable for a child based on the typical adult weight of 150 Ib (or 70 kg
using the metric equivalent of this equation).
2. Young’s rule,
Child's age (yr)
x Adult dose = Child's dose
Child’s age + 12 (yr)
calculates the dose for the child based on age, with a
12-year-old receiving half of the adult
dose.
3. Surface area, extrapolated from the patient's height and weight, is divided by the average
adult surface area to determine the fraction of the adult dose.
Geriatric pharmacology
The terms 'ageing' and 'senescence' are often used interchangeably. Both are characterized by
progressive changes in the tissues or organs of the body, leading to a decline in function and
death. Some of the common features associated with ageing include loss of skin elasticity,
decline in muscular strength, loss of hair, decline in immune competence, development of
atherosclerosis and cataract formation. Most of these recognizable features occur after
reproductive activity has ceased and the term 'senescence' is often used to describe this period,
which is associated with degenerative changes related to the passage of time. 'Ageing' in
contrast refers to any time-related process and could be said to begin at conception.
Drug metabolism in the elderly is presently characterized by:
 A decrease in liver blood flow (approximately 20-40%)
 A decrease in liver size (range 17-36%)
 No change in routine clinical tests of liver function
 Global metabolic liver function tests (antipyrine clearance, aminopyrine breath test)
might suggest some minor/neglectable decline in hepatic elimination
 Activities and expression of the hepatic enzymes involved in oxidative phase I
reactions (different CYP-isoforms) and conjugating phase II pathways are not
significantly impaired
 the clearance of most compounds tested does not change significantly.
 For high-clearance drugs, their elimination might be somewhat reduced secondary to a
reduction in hepatic blood flow
 Glucuronidation is well preserved
 Enzyme induction is still effective
Why all clinicians should be alert to the drug combinations that may pose particular dangers,
namely:
 Inhibitors and inducers of the hepatic monooxygenase system. Examples of common
inhibitors would include amiodarone, fluconazole, miconazole, ketoconazole,
erythromycin, clarithromycin, sulphonamides, cimetidine and ciprofloxacin.
Examples of common inducers are rifampicin, phenobarbital, phenytoin, primidone and
carbamazepine.
 Any drug combination causing hypotension,whether prescribed primarily for
cardiovascular disease or for other reasons. For example, 2 or more of the
following groups: tricyclic antidepressants, nitrates, calcium antagonists, ACE inhibitors, aadrenoceptor antagonists (a-blockers), antipsychotics and antiparkinsonian agents.
 Any combination of drugs causing additive sedative effects, which may lead to falls,
confusion, aspiration pneumonias, dizzy spells, apathy and incontinence.
 Combinations of drugs causing anticholinergic effects,such as antipsychotic
medications, some antiarrhythmic preparations, some tricyclic antidepressants, some
antihistamines and some antiparkinsonian agents.
 Any drug with a narrow therapeutic index, such as theophylline, phenytoin or
digoxin.
 Any elderly patient receiving coumarin anticoagulants.
Therapeutic Drug Monitoring (TDM) in the elderly is advised for antiarrhythmic drugs,
anticonvulsants, some antibiotics and antineoplastic agents. In addition, it is proposed to use
TDM to control therapy with antidepressants and antipsychotics. The arguments for
monitoring plasma drug concentrations in the elderly include:
 the increased risk of adverse drug reactions and drug interactions in this group
 situations where a patient's verbal skills are impaired such that they cannot
communicate any adverse effects they may be experiencing
 situations in which rapid changes in bodyweight or kidney and liver function occur, as
in the course of diseases.
TDM is particularly important for drugs with nonlinear pharmacokinetics such as phenytoin
where it is difficult to achieve target plasma concentrations during dosage changes.
Defining what constitutes an inappropriate drug can be difficult. The following criteria for
classifying a drug as inappropriate for use in elderly patients are:
 Specific medications or classes of medications that should not be used routinely in
elderly persons. This may be due to lack of proven drug effect, a high likelihood
of adverse drug effects, the potential for severe adverse effects, or a high potential for
interaction with another drug or class of drugs.
 Specific medications or classes of medications that should not be used routinely in
elderly persons with specific disease states. Some drugs pose an increased risk for
selected individuals with various medical conditions.
 Specific medications that have a risk of producing a serious adverse effect when safer
alternatives are available.
 Excessive dosages of medications used in elderly patients. Some medications for
elderly patients are safe when used in lower doses but increase the risk of
problems when used in higher doses.
 Excessive dosing frequencies that would make compliance difficult for elderly
patients. Because elderly patients tend to take multiple medications, it is
best to prescribe medications that have once-daily dosing when possible.
 Extended duration of use of medications that were intended to be used for a limited
time.
Many drugs considered inappropriate for elderly persons produce anticholinergic effects.
Often, these effects tend to be no more than a nuisance, although at times they can be rather
serious. Early effects from anticholinergic drugs include dry mouth and impaired diaphoresis.
Moderate symptoms include increased thirst, tachycardia, and pupillary dilation.
Anticholinergic toxicity can include urinary retention, agitation, hallucinations, seizures,
cardiac arrhythmias, and heart block.
Postoperative delirium has been reported in elderly patients taking anticholinergic drugs.
Cognitive impairment also may occur. If used in patients with closed-angle glaucoma, these
drugs substantially increase intraocular pressure that may threaten vision if not treated
urgently. Anticholinergic toxicity occurs more often when 2 or more anticholinergic drugs are
taken together.
Tricyclic antidepressants . These drugs have high lipid solubility. In the elderly population,
TCAs have an increased volume of distribution due to age-related pharmacokinetic changes.
They also tend to bind extensively to plasma proteins. Metabolism varies 10- to 30-fold from
one individual to another, and elimination of TCAs slows with age.
As a result, elderly patients who receive typical doses of TCAs usually develop higher plasma
drug levels and metabolites than do younger patients. All TCAs produce various degrees of
anticholinergic activity and frequently cause problems in elderly patients. The tertiary
amines, including amitriptyline, imipramine, and doxepin, produce a greater amount of
anticholinergic activity than the secondary amines nortriptyline and desipramine. If use of a
TCA is necessary, nortriptyline and desipramine, are preferred agents for elderly
patients.
Cardiac toxicity, the most serious complication from TCAs, is more likely to occur in
persons with preexisting cardiac disease. Tricyclic antidepressants can slow intraventricular
conduction and can produce 2:1 or 3:1 heart block and complete heart block. Persons with
preexisting cardiac conduction delay are at increased risk. Like quinidine, TCAs produce
antiarrhythmic activity and often suppress ventricular ectopy. Also like quinidine, TCAs
produce proarrhythmic activity and can cause ventricular arrhythmias, which may be fatal.
The most common potentially serious adverse effect from TCAs is orthostatic hypotension,
which becomes more common with advancing age and can occur even when these drugs are
used in low doses. The risk of orthostatic hypotension is less with nortriptyline.
Tricyclic antidepressants also can cause central nervous system (CNS) effects such as
confusion and seizures, which occur more commonly in elderly persons. Cognitive
impairment tends to be worse in those with some degree of underlying dementia. Use of
TCAs also can be associated with gastrointestinal (GI) and urinary effects. As a result of the
anticholinergic effect, gut motility can decrease, leading to constipation problems. Impairment
of urinary bladder contraction can result, producing urinary retention. Tricyclic
antidepressants can increase intraocular pressure and should not be used in patients with
closedangle glaucoma.
The literature contains ample evidence that traditional antipsychotic medications are
potentially inappropriate for elderly patients.
 Antipsychotic medications are occasionally prescribed to elderly patients, especially
those with behavior problems associated with dementia.
 The traditional antipsychotics produce either anticholinergic effects or have the
potential to produce extrapyramidal effects.
 Tardive dyskinesia represents the most serious adverse effect from antipsychotic
medications and can occur in elderly persons after short-term use and low doses.
 New-generation antipsychotic medications are available with efficacy similar to
traditional antipsychotics and with a greater safety record.
 Older antipsychotic medications should be considered inappropriate for elderly
patients.
 Barbiturates have been prescribed to elderly patients as both a sedative/hypnotic and
an anticonvulsant.
 Because of their high lipid solubility, barbiturates tend to have a prolonged duration
of activity in elderly persons and can easily lead to drug accumulation and toxicity.
 Tolerance to the sedating effects of barbiturates develops frequently, and often the
sedative effect is short-lived.
 Barbiturates suppress REM sleep, resulting in unnatural sleep.
 Barbiturates should be considered as inappropriate for the elderly population in most
circumstances (except as an anticonvulsant).
Ample evidence in the literature suggests that long-acting benzodiazepines are potentially
inappropriate for elderly patients.
 Benzodiazepines are effective sedative/hypnotic and antianxiety medications.
 Longer-acting benzodiazepines are highly lipid soluble with active metabolites,
which result in a long duration of activity in elderly patients.
 Short-acting benzodiazepines have low lipid solubility and no active metabolites,
which result in a short duration of activity in elderly patients; these drugs are
preferred when a benzodiazepine is indicated in elderly patients.
Adequate evidence supports the designation of diphenhydramine as a potentially
inappropriate medication for elderly patients. Patients with atopic illnesses such as urticaria or
allergic rhinitis or those who have primary dermatologic problems should use a secondgeneration antihistamine. Antihistamines such as fexofenadine, loratadine, and cetirizine
provide optimal antihistamine effect with no notable central effect. These medications do not
increase the risk of injury from motor vehicle crashes or from falls or impair cognitive
function in elderly patients.
 Older antihistamines such as diphenhydramine are often purchased over-the-counter to
treat insomnia and the symptoms associated with allergies.
 Diphenhydramine often produces sedation and has the potential to cause cognitive
impairment.
 When elderly patients need an antihistamine, newer products are available that do not
produce drowsiness and should be used instead of diphenhydramine and the other
older antihistamines.
Nonsteroidal anti-inflammatory drugs
 NSAIDs are prescribed frequently to elderly persons and notably benefit those with
painful conditions.
 NSAIDs have potential for serious GI, renal, and CNS effects.
 Because of the widespread use of NSAIDs in the elderly population, adverse effects
from NSAIDs may appear to be extremely common.
 Adequate data are unavailable to label the class of NSAIDs as inappropriate for use in
the elderly population.
 NSAIDs should be used judiciously and in low doses if possible by elderly persons.
 Alternatives to NSAIDs should be tried before giving elderly patients long-term
NSAID therapy.