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RESPONSIVENESS TO DRUGS

AT EXTREMES OF AGE

K. ü'MALLEY &J. G. KELLY

Department ofClinical Pharmacology.

Royal College ofS urgeons in Ireland.

St. Stephen 's Green.

Dublin 2. Eire

Introduction

In general , responsiveness to drugs depends on a combination of pharmacokinetic

and pharmacodynamic factors. The pharmacokinetic factors are those which govern

the absorption of drugs, transport to their sites of action, distribution to various

tissues, metabolism and elimination. The pharmacodynamic factors are those which

govern the type, intensity and duration of action of drugs. Studies on drug responses

at extremes of age must examine both sets of factors . Increased central effects of a

drug could be due to either increased penetration into the central nervous system or

to altered tissue response, Pharmacokinetic processes are of course easier to study

particularly with the advent ofincreasingly sensitive and specific methods ofmeasuring drugs and their metabolites in biological fluids. These studies are also easier in

adult subjects since it is of course easier to obtain repeated adequate blood sampIes.

As a result there is a relat ive abundance of pharmacokinetic studies in the elderl y.

However, even in infants and children increasingly complex pharmacokinetic studies

can be attempted as more sophisticated methodology allows the use ofsmall sampIes

ofblood.

In the elderl y, pharmacokinetics of drugs are becoming increa singly predictable

and some general rules are emerging .

I) Absorption ofdrugs does not greatly differ in old age.

2) In the case of drugs with considerable binding, there is a slight decrease with

advancing age, where the drug binds to albumin but binding increases where the

drug binds to n r-acid glycoprotein.

3) The 'first pass' effect is decreased in old people , resulting in increased systemic

availability ofhigh 'first pass' drugs.

4) Renal elimination falls in proportion to the decrease in renal function with ageing.

While the picture is by no means complete for infants and children, the variations in

drug metabolic and excretory processes in infanc y and childhood have been exten -

sively studied. Drug dispo sition at both extremes ofage is dealt with in more detail in

other contributions to this section.

Pharmacodynamics at extremes ofage have been little studied, and such studies as

have been carried out have dealt mainly with the elderly . The reason for lack of

DRUG RESPONSE AT EXTREMES OF AG E 125

published data, as for many other poorly studied topics, is a combination of unfashionability and lack ofsuitable techniques. Studies on drug response in man often

require the use ofinvasive techniques with their attendant ethical problems, especialIy in children. Most studies on drug response in adults have concentrated on the

cardiovascular system because ofthe relative ease ofmaking accurate measurements

in this system.

Pharmacodynamic differences may occur at various points between druglreceptor

interactions and the fmal pharmacological effect. Receptor density or receptor

characteristics may change. The mechanisms governing these are being siudied in

many laboratories. Recently it has become known that receptors are in a dynamic

state and that available receptor numbers can be altered qu ite rapidly both by physiological and pathological processes and by the presence of drugs . The translation of

the receptor-initiated response into a biochemical sequence producing a physiological effect may change. In addition alterations in the response of a tissue to this

biochemicall y initiated sequence may occur. Th is may be biochemical (for example,

glycogenolysis) or mechanical (for example, vascular relaxation). There are many age

related alterations in homeostatic control mechanisms and fmally different disease

processes occur at extremes of age.

The very young

There are a number of anecdotal examples of altered drug sensitivity but most have

little hard evidence to support them. The percentage of paediatric hospital

admissions due to adverse drug reactions is probably similar to that in adults. A three

year prospective study of 3556 paediatric admissions to hospital (McKenzie,

Marchall, Netzloff& Cluff, 1976)showed that 2% ofthese admissions were the result

of adverse drug reactions. This result is similar to that ofCaranasos, Stewart & Cluff

(1974) who showed that of4153 hospital admissions aged 11-60 years, 2.5% were due

to adverse drug reactions. For adverse drug reactions occuring in hospital, the Boston

Collaborative Drug Surveillance Program (1972) reported an incidence of approximately 13% in patients aged up to 12 years . While comparisons between centres in

this field are fraught with pitfalls it is noteworthy that Klein, Klein, Sturm, Rothenbuhler, Huber, Stucki, Gikalov, Keller & Hoigne (1976) found similar values for

patients aged between 15 and 54 years . The spectrum of disease in children however

is different to that in adults and this is reflected in different indications for therapy

and a different pattern of adverse drug reactions. Children receive fewer drug

exposures than adults (Boston Collaborative Drug-Surveillance Program, 1972) and

on the occasions when treatment is necessary it is more often for severe illness requiring more aggressive therapy than for adults. Thus, common indications for treatment

in children are infections, seizures and the pattern of drug use reflects this.

The optimal dail y dose of thyroxine required for replacement therapy in hypothyroidism in children is higher than in adults probably because hypothyroidism in

adults usually results from a partialloss ofthyroid function while in children there is

more likely to be a total loss of thyroid function (Rezvani & Di George, 1977). A

child's growth and maturing processes are critically dependent on a properly

functioning endocrine system and the use of drugs affecting this (adrenocorticosteroids) must be undertaken with care .

Cardiovascular drugs

At various times an increased sensitivity to parasympathomimetic agents and an

increased tolerance to sympathomimetic agents in young children has been reported.

However Lipton, Steinschneider & Richmond (1965) stated that much ofthe specula-

126 K . O'MALLEY & J. G. KELLY

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weight or body surfaee area basis) than adults. To a large extent this seems to be

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