A. Douglas Bender

EFFECT OF AGE ON INTESTINAL ABSORPTION: IMPLICATIONS FOR DRUG ABSORPTION IN THE ELDERLY

Studies dealing with the influence of increasing age on intestinal absorption are reviewed. Interest in these studies has resulted from statements that increasing age is accompanied by a delay and a reduction in drug absorption. There are, however, no data to support this conclusion. Nevertheless, data from studies of the absorption of sugars, fats and vitamins in subjects of different ages may be relevant to the problem of drug absorption, as are the other changes in gastrointestinal function that occur with advancing age. In the elderly there is a reduction in gastric pH which, in the case of some drugs, affects the solubility and thus will influence the rate of absorption. Furthermore, there is a reduction in intestinal blood flow, which would tend to delay or reduce drug absorption. Possibly there is a reduction in the number of absorbing cells in the intestine, with a consequent loss of absorbing surface in the aged; this may explain the reported reduction in passive diffusion in the aged. A modification of special transport mechanisms is suggested by the fact that the absorption of galactose, 3‐methyl glucose, calcium, and thiamine is reduced with increasing age. All of these factors tend to imply that drug absorption in the elderly is reduced. Fortunately perhaps, the reduction in absorption is accompanied by decreased metabolism and decreased excretion. Thus, limited absorption from the intestine is balanced by delayed elimination of drugs.

PHARMACOLOGIC ASPECTS OF AGING: A SURVEY OF THE EFFECT OF INCREASING AGE ON DRUG ACTIVITY IN ADULTS.

With increasing age, physiologic and pathologic changes occur which may profoundly affect the pharmacologic activity of drugs. Indeed Lasagna (1) has stated that “it seems almost ridiculous to suggest that aging should not affect drug responses.” Studies of alterations in drug activity with age, however, have been primarily concerned with differences in responses exhibited by the infant and the adult; few such comparisons between adults of different ages are available (2). Because of this lack of data, previous discussions (1, 3-12) have been limited to clinical observations in man or to a brief review of experiments performed in animals. Recently, however, more animal studies have been reported, and also a greater interest has been shown in drug therapy in the aged. This increased interest is due, for the most part, to the large number of active agents introduced within the past decade and to a greater concern for the welfare of the growing geriatric population. The present paper is a survey of observations made in man and animals with respect to the modification of drug activity with increasing age, from the young adult to the elderly. This survey is presented in an attempt to stimulate further interest in the study of the role of aging, to point out the difficulties in initiating and conducting such studies, to provide a background of results previously reported, and to stress the lack of studies in man. Particular emphasis has been placed on changes exhibited in old age. No attempt will be made to review therapeutic efforts to slow or retard the aging process (13-16) or the abuse of drugs by the elderly (17, 18).

Pharmacodynamic Principles of Drug Therapy in the Aged

The geriatric patient responds differently to some drugs than does the younger adult, and consequently certain precautions should be taken when prescribing a therapeutic regimen for the elderly. Increasing age is accompanied by functional changes in many of the systems that control the way a drug is metabolized and the response that it evokes. Apparently it is these changes which underlie the modified effect seen clinically in geriatric patients. Age tends to reduce and delay the absorption of substances from the gastrointestinal tract, impair and delay drug clearance and excretion by the kidneys, and reduce the rate of enzyme destruction. The plasma half‐life of penicillin, digoxin, antipyrine, or phenylbutazone is extended significantly in the aged so that higher circulating concentrations are maintained for longer periods. Other age‐related changes influence the effect of a drug once it has combined with its receptor. These include an altered number of receptor sites, a decrease in the transmitter content of affected tissues, an increase in the rigidity of responsive tissues, and an overall decline in homeostatic capability.

Delphic study examines developments in medicine

Abstract This experiment with the Delphi forecasting technique correlates the opinions of experts about likely developments in the field of medicine. The study was conducted for a report by Smith Kline & French Laboratories in the USA as an aid to the planning of a pharmaceutical company. Two internal questionnaires encouraged the formulation of an extramural Delphi to probe the future of five areas, biomedical research, diagnosis, medical therapy, health care and medical education. The results of the survey are displayed graphically, and a scenario for the years 1978–1983 has been constructed from the consensus statements.

Inhibitory effects of aspirin and indomethacin on the biosynthesis of PGE2 and PGF2α

Abstract A gas-liquid chromatography system has been used to study the effects of indomethacin and aspirin on the biosynthesis of PGE2 and PGF2α by the prostaglandin synthetase system of bovine seminal vesicle. Both compounds were found to inhibit the production of PGE2 and PGF2α. However, based on statistical analyses, the inhibitory effect of indomethacin was found to be non-selective while aspirin produced statistically significant preferential inhibition of PGE2 over PGF2α.

Changes in serum potassium levels occurring in patients treated with triamterene and a triamterene‐hydrochlorothiazide combination

This report summarizes the changes in serum potassium levels in 583 patients treated with triamterene alone, 484 treated with a combination of triamterene and hydrochlorothiazide, and 82 treated with hydrochlorothiazide. The incidence of hypokalemia <3.5 mEq. per liter) in patients treated with a combination of triamterene and hydrochlorothiazide was 6 per cent. Hyperkalemia (>5.4 mEq. per liter) developed in 7.5 per cent of subfects to whom the combination was given, in 12 to 19 per cent of subfects treated with triamterene, and in 4 per cent of patients, especially the severely ill, treated with hydrochlorothiazide.

A pharmacodynamic basis for changes in drug activity associated with aging in the adult

Abstract The information available in the literature suggests that age has an effect on various organs and tissues responsible for drug handling and that these changes are reflected in altered drug activity. It has been suggested that drug absorption is slower and less complete in the older animal and that once absorbed there is delayed distribution of the agent. Plasma levels of the drug may achieve higher levels in the older animal due to the delayed excretion and slower metabolic inactivation. These changes will also result in a longer duration of activity. The response to a drug is dependent not only on the amount of drug made available to and in equilibrium with the receptor site but also on the state of the receptor site itself. There is evidence to suggest that with increasing age there are a fewer number of active receptor sites available, and thus, the sensitivity to a drug may be depressed or enhanced depending on the action of the drug, whether it acts in a positive manner or produces its effect as a result of inhibition. The over-all response to a drug is a reflexion not only of the sum of these influences but of the ability of the organism to adjust to the internal change induced by the drug. Drug effects may be more pronounced in the older animal because of limited homeostatic mechanisms. In the review it was pointed out that these observations are based on very limited experimental data and that additional work is necessary to expand our knowledge of the effect of age on drug activity.

The influence of age on the activity of catecholamines and related therapeutic agents.

A review has been made of the literature on the changes with age in the sensitivity of various organs and tissues to catecholamines. The objective of this review was to examine these changes and to interpret them in the light of related compounds that are employed commonly in the treatment of the elderly. The available evidence strongly indicates that there is an increase with age in the sensitivity to exogenously administered amines. In terms of the therapeutic application of related drugs in the elderly, this finding indicates that caution should be used when administering such agents, particularly if they have significant secondary effects which are related to the stimulation of adrenergic receptors. Additional information indicates that perhaps there is a delay in the excretion and in the distribution of catecholamines. Thus, higher blood levels might be anticipated when sympathomimetic amines are employed in the treatment of various disease states.

USE OF A DIURETIC COMBINATION OF TRIAMTERENE AND HYDROCHLOROTHIAZIDE IN ELDERLY PATIENTS

As our elderly population increases in numbers and in age, so too does the need for treating diseases of the aged, and therefore the need for special knowledge of drug efficacy and drug safety in the aged. For that reason, the clinical and laboratory data reported here, obtained by 80 investigators in the course of studying an investigational diuretic in 549 elderly patients, may be of value. When using diuretics to treat edema in elderly patients, one must keep in mind that there have been reports of a progressive decrease in the glomerular filtration rate (GFR) (1) and urea clearance (2) with aging. These findings take on added interest in the light of evidence that presently available diuretics produce a slight depression in GFR (3, 4) and that the effectiveness of hydrochlorothiazide is impaired when GFR is markedly reduced ( 5 ) . Whether these observations are clinically important is not yet clear; the results of several studies on diuretics and diuretic combinations would indicate that they are not. But there seems to be some reason for concern in view of the relationship that exists between GFR and blood urea nitrogen (BUN) levels. Because mathematically the product of blood urea concentration and urea clearance is equal to a constant rate of excretion for a given protein intake (6) , a plot of the blood urea level and urea clearance yields a rectangular hyperbola. Urea clearance is proportional to the rate of glomerular filtration (7) so that a similar curve is obtained when the blood urea nitrogen level is plotted as a function of the gloinerular filtration rate. In more clinical terms, a reduction in GFR is reflected in an elevation in BUN. From the standpoint of efficacy this would suggest that diuretic agents might be somewhat less effective in an elderly patient with a marked reduction in GFR. From the standpoint of safety, a fall in GFR in an elderly patient would be accompanied by a greater BUN rise than would accompany a similar fall in a younger patient. The thiazide diuretics cause potassium loss (8), a loss which is not always symptomatic but, in cardiac patients, results in a greater sensitivity to the toxic effects of digitalis (9). In the elderly patient receiving a thiazide this is significant (10) because the senile heart is more sensitive to the actions of the cardiac glycosides (11) and because the aged may be more likely to develop symptoms of potassium depletion (12). One reason for investigating a combination of triamterene and hydrochloro-

A very early warning system for the rapid identification and transfer of new technology

The article describes the structure and mechanism of a Very Early Warning System (VEWS) which was devel‐oped as a tool for the early recognition and transfer of new technology, affecting both present and future R&D activities in the pharmaceutical sector. The VEWS de‐scribed is concerned with the collection, interpretation, analysis, and exploitation of new data from the world‐wide scientific and patent literature, scientific meetings, government reports, and personal communications. Sys‐tems activities are grouped into four phases: data acquisition, data expansion, critical analysis, and data exploitation. Iterative processing of an expanding com‐puterized data base is a key feature of the system.