Figure 1 Specific binding of digoxin to erythrocytes from neonates and adults. a) Numbers of
digoxin molecules bound per erythrocyte, b) dissociation constant for digoxin binding (from
DRUG RESPONSE AT EXTREMES OF AGE 127
ratio and a threefold higher erythrocyte/plasma concentration in infants. It was
recently shown (Kearin, Kelly & O'Malley, 1980)that the number of specific digoxin
binding sites on erythrocytes, commonly equated with Na+,K+· ATPase sites, from
neonates is two to three times that in adults and that the binding has a lower affmity
(Figure la and b). Ifthe erythrocyte Na+,K+· ATPase reflects the myocardial situation
our fmdings are consonant with there being a decrease in intrinsic sensitivity to
Qualitative changes in response to amphetamine and phenobarbitone are weil
known. Thus amphetamine has a paradoxical sedating effect in 'hyperactive'
children. Phenobarbitone on the other hand is said to produce hyperactivity in
children although there has been little detailed investigation of the underlying
mechanism or indeed ofits true prevalence . One placebo controlled study in children
treated with phenobarbitone for febrile seizures (Carnfield, Chaplin, Doyle, Shapiro,
Cummings & Carnfield, 1979) reported increased daytime 'fussiness', 'irritability'
and a sleep disturbance. Qualitative differences in response to other anticonvulsants
have not been reported. It is difficult to say ifthe spectrum ofside effects produced by
these drugs changes in children. Nystagmus due to diphenylhydantoin has been said
to occur only infrequently in children but may be seen when blood levels are in the
therapeutic range (Berman, 1976). This suggests that observed lack of nystagmus
reflects underdosage in children.
There are significant and interesting differences in response to neuromuscular
blocking drugs in children (Nugent, Laravuso & Rogers, 1979). Neonates have an
increased responsiveness to nondepolarizing blocking drugs such as tubocurarine. On
the other hand infants and young children are more resistant than adults to the
neuromuscular block produced by the depolarizing muscle relaxants such as
succinylcholine and decamethonium. Muscle fasiculations following succinylcholine
are generally not apparent in young children. The reasons for these differences are
unknown. There are also significant differences in effects of spinal anaesthesia in
children, the time to regain motor function after spinal anaesthesia being less (Dohi,
Increases in adverse drug reactions with age have been observed both in hospitalised
patients (Klein et al., 1976; Seidl, Thornton, Smith & Cluff, 1966) and in patients
requiring admission to hospital (Hurwitz, 1969; Caranasos et al., 1974). While
increased levels of free drug at the site of action probably are important with some
drugs and also there is more prescribing in the elderly, it seems likely that for many
drugs there is an increased susceptibility to adverse drug reactions . The role of
pharmacodynamics in this is not clear.
Recent advances in understanding the basic mechanisms ofdrug action , especially
at the receptor level, are being increasingly applied to old age. As a result significant
advances are being made in understanding the pattern of effect of drugs, especially
cardiovascular drugs in the elderly.
In recent years a significant amount of work has been published dealing with
alterations in ß-adrenoceptor function in ageing animals. Results of these studies
have suggested possible investigations in man and have enabled clarification ofsome
meehanisms underlying ehanges in adrenergic funetion in old age.
Work in animals has suggested deereases in adrenergieally produeed metabolie and
tissue eontraetile responses with inereasing age (Fleish, Maling & Brodie, 1970;
Lakatta, Gerstenblith, Angeli, Shoek & Weisfeldt, 1975; Bitensky, Russell & Blaneo,
1970). These ehanges seem to refleet deereases in adrenoeeptor density (Bylund,
Tellez-Inon & Hollenberg, 1977; Greenberg & Weiss, 1979). In addition the ability of
ageing tissues to alter reeeptor density is attenuated. Greenberg & Weiss (1979) have
shown that while aged rats ean deerease ß-adrenoeeptor numbers in response to
noradrenaline by reserpine. Their data also support the hypothesis that numbers of
Similar observations have been made in man . Deereases in noradrenaline-indueed
lipolysis in isolated fat eells oeeur in old age (Berger, Preiss, Hess-Wortman & Gries ,
1971). It has been shown (Figure 2) that isoprenaline-stimulated produetion of eyclie
AMP by isolated human lymphoeytes is markedly redueed in the elderly (Dillon,
Chung, Kelly, & O'Malley, 1980).One report (Shoeken & Roth, 1977)has deseribed a
deerease in numbers of Iymphoeyte /J-adrenoeeptors with advaneing age. Bertel,
Figure 2 Cyclic AMPproduction resulting from isoprenalin e stimulation oflymphocytes from
young and elderl y subjects (from Dilion et al., 1980).
DRUG RESPONSE AT EXTREMES OF AGE 129
min-I increases with advancing age in both normal and hypertensive subjects.
Vestal et al. (1979)further demonstrated that resistance to the efTects of propranolol
increases with age. These results suggest that there is a generalised decrease in
ß-adrenoceptor-mediated function in old age.
Many of the above changes will be reflected in alterations in cardiovascular function
and in the efTects of drugs on this system . In addition, however, structural changes in
blood vessels might account for a mechanical limitation to drug response (Tuttle,
1966). Diminutions in cardiovascular homeostatic function with age may complicate
Pharmacokinetics of digoxin change markedly and predicably with advancing age
(Cusack, Kelly, O'Malley, Noel, Lavan & Horgan, 1979) but there is little evidence
to suggest that intrinsic response to digoxin changes. There are no alterations in
specific tissue binding properties of ouabain in old age (Erdmann & Hasse, 1973)and
this probably also applies to digoxin. Increased incidence ofhypokalaemia especially
during diuretic treatment would lead to an increase in toxicity of digoxin but there is
little recent evidence to suggest that either of these occurs preferentially in the
elderly . While there appear to be no major age related changes in pharmacokinetics
ofwarfarin, the elderly are subject to a higher degree of anticoagulation with this drug
(O'Malley, Stevenson, Ward, Wood & Crooks, 1977). This appears due to an
increased inhibition of vitamin K dependent clotting factor synthesis in the elderly
(Shepherd, Hewick , Moreland & Stevenson, 1977).
Elderly people are often thought to be particularly sensitive to the central nervous
system depressant efTects of drugs. Possible reasons are, a) increased penetration of
drugs into the central nervous system (CNS), b) reduced elimination of CNS active
in old age, there is little known ofthe role ofthe remaining two factors . In any event it
would be difficult to distinguish between alterations in distribution of drug and
A standard dose of pethidine produces higher plasma concentrations in e1derly
The benzodiazepines are among the drugs most prescribed in the elderly. A study
by Castleden, George , Marcer & Hallett (1977) compared the efTects of nitrazepam
and placebo on psychomotor performance in young and elderly subjects. Thirty six
hours after nitrazepam the old people made twice as many mistakes than on placebo
while there was no difTerence between the efTects of nitrazepam and placebo in the
similar in both age groups . These results suggest an increase in efTect ofnitrazepam in
sensitivity. Hewick & Shaw (1978) administered the same dose of 14C labelIed
nitrazepam to young and elderly rats . The plasma concentration, plasma c1earance,
plasma half-life and apparent volume of distribution were similar in both groups .
However, the sedative efTect was greater in the old rats and the concentrations of
radioactivity in brain tissue from the old rats were two to three times greater than in
130 K . O'MALLEY & J. G. KEL LY
H yperten sion occ urs at all ages but poses special probl em s in the elde rly, Wh ile th e
association between high blood pr essure an d cardiovascul ar risk is weil establ ished it
is not kn own at what leve l ofblood pressure drug treatment is of'be nefrt to the elde rly
pat ient. It see ms likely th at in th e elderly high blood pressure has a di fferent ba sis to
th at occ urri ng in younger adults. Systolic hypertension dom inate s since many
pat ients have d isproportionat ely high systolic pressure (SP) co m pa red with diastol ic
pr essure (D P), Koch -Weser (1973) has defmed disproportion at e systolic hypert ension
as SP > (D P - 15) x 2. This is du e to a decrease in a rterial compliance , a disorder
which see ms at least in part to be reve rsible (Simon, Safar, Levenson , Kh eder &
Levy, 1979). Also th e best mean s of lowering blood pr essure in th e elde rly is not
In sum ma ry, at both extremes of age th ere are changes in drug dispo sition wh ich
acc o unt for some changes in the magnitude and durat ion of drug effect. Relatively
littl e is kno wn of cha nges in intrinsic responsiven ess but our kn owledge of
ß-ad renoceptor med iat ed effects suggests a dimin ished responsiveness in the elderly .
H ypert ension is an excelle nt exa mple of a disorder in which th e pathogene sis is
d ifferent in eac h age gro up, particul arl y in th e case of th e elde rly , where littl e
is known of the disp ositi on or ph a rm acod ynamics ofantih ypert ensive drugs.
Ou r know ledge of drug effects is gro ssly de ficient in th e elde rly, but th is is even
mo re so in th e very young. W hile there are man y co nstraints on resea rch int o drug
effects particul arl y in th e yo ung it is difficult to escape the conclu sion tha t th e relative
plethora of ph a rm acokinet ic studies reflects the ease with whic h they ca n be don e
whereas th e study of drug effects awaits the atte ntion of more dete rmined c1inical
ph armacologists. On ly when ma ny more studies on drug effects are ca rried out in th e
releva nt c1 inic al setti ng will it be possible to approach thera pe utics in very young and
very old pat ients with co nfidence .
Berger, M., Preiss, H., Hesse-Wortman. C. & Gries, F. A. (1971). Norepinephrine-lipolysis in
isolated fat cellsof non-obese aged humans(72 yr). Gerontol., 17, 312-322 .
Berman, P. H. (1976). Management of seizure disorders with anticonvulsant drugs. Current
concepts. Ped. Clin . N. Am., 23,443-45 9.
Bertel, 0 ., Buhler, F. R., Kiowski, W. & Lutold, B. E. (1980). Decreased beta adrenoceptor
responsiveness as related to age, blood pressure and plasma catecholamines in patients
with essential hypertension. Hypertension. 2, 130-138.
Bitenskyu, M. W., Russell, V. & Blanco, M. (1 970). Independent variation of glucagon and
epinephrine responsive components of hepatic adenyl cyclase as a function of age, sex and
steroid hormones. Endocrinology. 86,1 54-159 .
Boston Collaborative Drug Surveillance Program. (1972). Drug Surveillance: Problems and
Challenges. Ped. Clin. N. Am ., 19, 117-1 29.
Bylund, D. M., Tellez-lnon, M. T. & Hollenberg, M. D. (1977). Age-related parallel decline in
Camfield, C. S., Chaplin, S., Doyle, A. B., Shapiro, S. H., Cummings, C. & Camfteld, P. R.
(19 79). Side elTects of phenobarbital in toddlers: behavioral and congenitive aspects. J.
DRUG RESPONSE AT EXTREMES OF AGE 131
Castleden, C. M., George, C. F., Marcer, D. & Hallett, C. (1977). Increased sensitivity to
nitrazepam in old age. Brit. med. J., 1, 10-12.
Chan, K., Kendall, M. J., Mitchard, M., Wells, W. D. E. & Vickers, M. D. (1975). The efTect of
ageing on plasma pethidine concentration. Brit. J. c1in. Pharmac., 2,297-302.
Cusack, B., Kelly , J. G ., O'Malley, K., Noel, J., Lavan, J. & Horgan, J. (1979). Digoxin in the
elderly: Pharmacokinetic consequences ofold age. Clin. Pharmac. Ther., 25, 772 -776.
Dillon, N., Chung, S., Kelly. J. & O'Malley. K. (1980). Age and beta adrenoceptor-mediated
function. Clin. Pharmac. Ther.. 27, 769-772.
Dohi, S., Naito, H. & Takahasi, T. (1979). Age-related changes in blood pressure and duration of
motor block in spinal anaesthesia. Anaesthesio/., 50,319-323.
Erdmann, E. & Hasse, W. (1973). Quantitative aspects ofouabain binding to human erythrocyte
and cardiac membranes. J. Physiol., 251,671-682.
Fleish , J. H., Maling, H. M. & Brodie , B. B. (1970). Beta receptor activity in aorta: variations
with age and species. Circu/ation Res., 26,151-162 .
Gorodischer, R., Jusko, W. J. & Yaffe, S. J. (1976). Tissue and erythrocyte distribution of
digoxin in infants. Clin. Pharmac. Ther., 19,256-263.
Greenberg, L. H. & Weiss, B. (1979). Ability of aged rats to alter beta adrenergic receptors of
brain in response to repeated administration of reserpine and desmethylimipramine. J.
Pharmac. exp. Ther., 211,309-316.
Hewick, D. S. & Shaw, V. (1978). Tissue distribution of radioactivity after injection of I4C
nitrazepam in young and old rats. J. Pharm. Pharmac., 30, 318-319.
Hurwitz, N. (1969). Admissions to hospital due to drugs. Brit. med. J., 1,539-540 .
Kearin, M., Kelly, J. G. & O'Malley, K. (1980). Altered digoxin 'receptors' in neonates: an
explanation ofdecreased sensitivity to digoxin? Clin. Pharmac. Ther., in press .
Klein , U., Klein, M., Sturm, H., Rothenbuhler, M., Huber, R., Stucki , P., Gikalov, 1., Keller,
M. & Hoigne, R. (1976). The frequency of adverse drug reactions as dependent upon age,
sex and duration ofhospitalization./nt. J. c1in. Pharmac., 13,187-195.
Lakatta, E. G. , Gerstenblith, G. , Angeli , C. S., Shock, N. W. & Weisfe ldt, M. L. (1975).
Diminished inotropic response of aged myocardium to catecholamines. Circu/ation Res.,
Lipton, L., Steinschneider, A. & Richmond, J. B. (1965). The autonomic nervous system in
No comments:
Post a Comment
اكتب تعليق حول الموضوع