Elsevier

Experimental Gerontology

Volume 38, Issue 8, August 2003, Pages 843-853
Experimental Gerontology

Review
When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly

https://doi.org/10.1016/S0531-5565(03)00133-5Get rights and content

Abstract

The age-related changes in the functions and composition of the human body require adjustments of drug selection and dosage for old individuals. Drug excretion via the kidneys declines with age, the elderly should therefore be treated as renally insufficient patients. The metabolic clearance is primarily reduced with drugs that display high hepatic extraction (‘blood flow-limited metabolism’), whereas the metabolism of drugs with low hepatic extraction (‘capacity-limited metabolism’) usually is not diminished. Reduction of metabolic drug elimination is more pronounced in malnourished or frail subjects. The water content of the aging body decreases, the fat content rises, hence the distribution volume of hydrophilic compounds is reduced in the elderly, whereas that of lipophilic drugs is increased. Intestinal absorption of most drugs is not altered in the elderly. Aside of these pharmacokinetic changes, one of the characteristics of old age is a progressive decline in counterregulatory (homeostatic) mechanisms. Therefore drug effects are mitigated less, the reactions are usually stronger than in younger subjects, the rate and intensity of adverse effects are higher. Examples of drug effects augmented is this manner are postural hypotension with agents that lower blood pressure, dehydration, hypovolemia, and electrolyte disturbances in response to diuretics, bleeding complications with oral anticoagulants, hypoglycemia with antidiabetics, and gastrointestinal irritation with non-steroidal anti-inflammatory drugs. The brain is an especially sensitive drug target in old age. Psychotropic drugs but also anticonvulsants and centrally acting antihypertensives may impede intellectual functions and motor coordination. The antimuscarinic effects of some antidepressants and neuroleptic drugs may be responsible for agitation, confusion, and delirium in elderly. Hence drugs should be used very restrictively in geriatric patients. If drug therapy is absolutely necessary, the dosage should be titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose.

Introduction

Most of us want a long life, but that implies getting old. Aging is associated with many disconcerting problems, not the least of which concerns the efficacy and safety of drug therapy. The increase in life expectancy over the past decades makes this issue more acute, survival to old age seems to be more and more the norm.

The beginning of senescence is insidious. Although this process commences after maturation, it manifests itself prominently and progressively in the post-reproductive stages of live. Society has agreed, rather arbitrarily, to define elderly as individuals aged 65 years and older.

This review deals with the principles of drug use in the elderly and the age-related alterations in drug disposition and response, changes that result from the modifications of the functions and composition of the body associated with aging. The literature on the topic is vast, so this article makes no attempt to be comprehensive.

Section snippets

Biology of aging

Survival to old age requires a protected habitat, as wild animals usually die early from extrinsic hazards such as infection, predation, starvation, or cold (Kirkwood and Austad, 2000). Aging entails a gradual decrease in physiological fitness and reduced ability to respond to environmental demands. The reduction in homeostatic capablities is a fundamental feature of senescence, but the decline in functional reserve varies markedly between elderly persons (Lamy, 1991, Troen, 2003, Turnheim, 1998

Pharmacokinetics

All stages of the journey of a drug through the human body may be affected by aging, the most important pharmacokinetic change in the elderly being the reduction in renal drug elimination.

Pharmacodynamics

The pharmacokinetic guidelines for dose adjustment in the elderly given above disregard changes in the sensitivity to an agent. Aside from its concentration at the site of action, the magnitude of a drug effect depends on the number of receptors in the target organ, the ability of the cells to respond to receptor occupation (signal transduction), and on counterregulatory processes that tend to preserve the original functional equilibrium. Thus, in addition to pharmacokinetics, the

Antiaging or longevity medicine

Antiaging is a hot subject these days and there is brisk commerce in remedies that claim to slow, stop, or even reverse the aging process. But in spite of considerable hype to the contrary, there is no scientifically valid evidence that antiaging drugs presently on the market (ginseng, garlic, ginko biloba, chondroitin sulfate, DHEA, growth hormone, melatonin, fish oil, St Johns wort, procain) can increase longevity (Platt, 1990, Turnheim, 1995, Olshansky et al., 2002). In some cases these

Conclusions

Persons aged 65 or older are particularly susceptible to adverse drug reactions because of multimorbidity, the high number of medications used in this population, and age-associated changes in pharmacokinetic and pharmacodynamic properties. The rate of adverse drug effects is estimated to be 2-3 times higher in older individuals than in adult patients younger than 30 years (Turnheim, 1998). As much as one fifth of all hospital admissions of older subjects are attributed to adverse drug effects

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