Agerelated Physiological Variation

From gestation to maturity, the growth and development of individuals are marked by changes in shape and size resulting from cellular multiplication and by structural and functional maturation. No sharp distinction between these processes is possible, but together they make up a complex set of factors whose combined significance is greater than either process alone. For certain tissues, the rate of change is rapid, as it is between birth and 2 or 3 years of age for neural tissue, or for lymphoid tissue toward the end of the first decade. For other tissues, rates of change are more gradual. Thus, while the relative proportions of skeletal muscle and subcutaneous tissue change markedly toward the end of the first decade, there is little alteration in the weight and height of the individual. When variations are large, averages tend to lose their significance and norms are better expressed as a range of values. For certain attributes, separate norms are needed for males and females, and at certain stages of childhood, such as the onset of adolescence, a profusion of physiological changes occurs with such rapidity that the gross features of a person, such as age or body weight, are of little use as scales of reference. Such profound physiological differences that are inherent in infancy and childhood cannot be disregarded in therapeutic management.

As individuals approach maturity, structural and functional changes abate.12 The problem of differentiating normal from abnormal development in the immature person is replaced later in life by the problem of sorting involutional from pathological change, especially at more advanced ages when morbidity is so common.13 Furthermore, certain maturational changes may continue in some tissues while involutional processes have already commenced in others. For instance, while most individuals reach sexual maturity by 15 years of age, the ability for visual accommodation has already begun to decline. Maturation and involution may even occur simultaneously as shown by the coexistence of atrophy and hypertrophy in the gastric mucosa, and certain types of degenerative changes appear to exhibit aging at a chemical level without accompanying histological changes, while the opposite occurs in other situations. Loss of near vision with advancing age exemplifies the former and disseminated cerebral atrophy, in which cells disappear but vital function is maintained, exemplifies the latter.

Variations in physiological functions of living organisms imposed by changes of size and shape have been examined intensively.14,15 The observation that certain functions may vary directly with body surface area was recognized and documented more than a century ago for numerous therapeutic and toxic agents.16 A nomogram based on this principle has been applied to the adjustment of drug dosage between individuals of different sizes and different ages.3 Its value in therapeutics stems from the observation that the extracellular water compartment, an important determinant of drug distribution, varies proportionately with its surface area. Consequently, drugs that are distributed in extracellular water would be expected to reach similar concentrations in persons of different sizes if they were dosed according to this principle. Dosages for drugs that are distributed in a space that exceeds the extracellular compartment cannot be estimated from the body area because the total body water, or any fraction in excess of extracellular water, does not vary in proportion to body area. The constitutional variability from one person to another suggests we adopt a conservative attitude toward extensions of this principle, particularly for extrapolations from mature individuals to infants and children.

Age-related changes in the time course of drug disposition (pharmacokinetics) and in the dynamics of drug responsiveness (pharmacodynamics) tend to occur in an orderly sequence at predictable stages in the life of individuals, but their onset and extent can vary widely from individual to individual. During infancy and childhood these changes are usually rapid and either periodic or cyclic, but throughout the adult years they are more gradual and progressive. With advancing age, a series of asynchronous anatomical and physiological effects occurs that results in increased interindividual variability. An accumulation of local effects at the molecular, cellular, and tissue levels impairs many regulatory processes that provide functional integration between cells and organs. The ability to maintain functional equilibrium through homeostatic mechanisms is reduced, which predisposes older persons to unusual or unexpected effects from several classes of drugs. Pharmacokinetic changes include a reduction in hepatic and renal clearance that prolongs drug elimination, while pharmacodynamic changes may alter the sensitivity to many drugs that are frequently used in older persons.

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