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Biomedical and Clinical Divisions, National Ageing Research Institute, University of Melbourne Department of Medicine and Melbourne Health Aged Care Services, Royal Melbourne and Mt Royal Hospitals, Melbourne Health and University of Melbourne, Parkville, Victoria, and John Curtin School of Medical Research, Institute of Advanced Studies, Australian National University, Canberra, Australian Capital Territory, Australia (A.J.M.); and Centre for Education and Research on Ageing and the ANZAC Research Institute, Concord Hospital, and University of Sydney, New South Wales, Australia (D.G.L.)
Abstract
Abstract I. Aging, Disease, and Drugs II. Biology of the Aging Process A. Oxidative Stress B. Mitochondria and Aging C. Telomeres and Cellular Senescence D. Apoptosis E. Genetic Mechanisms for Aging F. Caloric Restriction III. The Aging Process and Pharmacokinetics A. Drug Absorption and Bioavailability B. Volume of Distribution and Aging C. Hepatic Aging and Drug Metabolism 1. The Principles of Hepatic Drug Disposition. 2. In Vitro Studies of Aging and Hepatic Drug-Metabolizing Enzymes. 3. In Vivo Studies of Hepatic Drug Clearance in Humans. 4. Broader Implications of Liver Aging. 5. Aging Biology and the Liver. D. Renal Aging and Drug Elimination 1. Aging and the Glomerular Filtration Rate. 2. Aging and Renally Eliminated Medications. 3. Aging Biology and the Kidney. IV. The Aging Process and Pharmacodynamic Responses V. Clinical Implications of Aging Changes in Pharmacology A. Adverse Drug Reactions B. Evidence-Based Medicine in Older People VI. Conclusions
Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, "start low and go slow" is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.
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