Advertisement

Clinical Pharmacokinetics

, Volume 35, Issue 1, pp 49–64 | Cite as

Pharmacokinetic and Pharmacodynamic Changes in the Elderly

Clinical Implications
  • Andrea Hämmerlein
  • Hartmut Derendorf
  • David T. Lowenthal
Review Article Special Populations

Abstract

Age-related changes in pharmacokinetics principally affect drug absorption, distribution, metabolism and elimination. Changes in pharmacodynamics are primarily seen in the cardiovascular and neuroendocrine system. Age-dependent changes in the kinetics and dynamics of drugs acting on the cardiovascular system and central nervous system are common, and this review, while by no means exhaustive of the effects of drugs on all organ systems, is reflective of the principles and gives examples of the effects of age on these 2 major systems. While pharmacokinetic changes in the elderly are usually well characterised, pharmacodynamic changes are understood only in the most preliminary way. There has been relatively little research in this area of geriatric clinical pharmacology, and pharmacodynamic changes are still an area of investigation.

Keywords

Adis International Limited Digoxin Calcium Antagonist Prazosin Nitrazepam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Baum C, Kennedy D, Forbes M, et al. Drag use in the United States in 1981. JAMA. 1981; 251: 1293–7.Google Scholar
  2. 2.
    Shock N. Normal human aging: the Baltimore Longitudinal Study of Aging [Publication No. 84]. Washington, DC: US Government Printing Office, 1984: 2450.Google Scholar
  3. 3.
    Turner N, Scarpace PJ, Lowenthal DT. Geriatric pharmacology: basic and clinical considerations. Annu Rev Pharmacol Toxicol. 1992; 32: 271–302.Google Scholar
  4. 4.
    Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations: Pt I. Clin Pharmacokinet. 1991; 21(3): 165–77.PubMedGoogle Scholar
  5. 5.
    Delafuente JC. Perspectives on geriatric pharmacotherapy. Pharmacotherapy. 1991; 11(3): 222–4.PubMedGoogle Scholar
  6. 6.
    Colt HG, Shapiro AP. Drug-induced illness as a cause for admission to a community hospital [see comments]. J Am Geriatr Soc. 1989; 37(4): 323–6.PubMedGoogle Scholar
  7. 7.
    Vestal RE, Wood AJ, Shand DG. Reduced beta-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther. 1979; 26(2): 181–6.PubMedGoogle Scholar
  8. 8.
    Bender A. Effect of age on intestinal absorption: implications for drug absorption in the elderly. J Am Geriatr Soc. 1968; 16: 1331–9.PubMedGoogle Scholar
  9. 9.
    Geokas M, Haverback B. The aging gastrointestinal tract. Am J Surg. 1969; 117: 881–92.PubMedGoogle Scholar
  10. 10.
    Richey D, Bender A. Pharmacokinetics consequences of aging. Annu Rev Pharmacol Toxicol. 1977; 17: 49–65.PubMedGoogle Scholar
  11. 11.
    Evans M, Triggs E, Cheung M, et al. Gastric emptying rate in the elderly: implications for drug therapy. J Am Geriatr Soc. 1981; 29: 201–5.PubMedGoogle Scholar
  12. 12.
    Bender A. The effect of increasing age on the distribution of peripheral blood flow in man. J Am Geriatr Soc. 1965; 13: 192–8.PubMedGoogle Scholar
  13. 13.
    Evans M, Triggs E, Broe G, et al. Systemic availability of orally administered L-dopa in the elderly parkinsonian patient. Eur J Clin Pharmacol. 1980; 17: 215–21.PubMedGoogle Scholar
  14. 14.
    Castleden C, George C. The effect of aging on the hepatic clearance of propranolol. Br J Clin Pharmacol. 1979; 7: 49–54.PubMedGoogle Scholar
  15. 15.
    Larsson M, Landahl S, Lundborg P, et al. Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment. Eur J Clin Pharmacol. 1984; 27: 217–22.PubMedGoogle Scholar
  16. 16.
    Ho P, Triggs E. Drug therapy in the elderly. Aust NZ J Med. 1984; 14: 179–90.Google Scholar
  17. 17.
    Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982.Google Scholar
  18. 18.
    Peck C. Bedside clinical pharmacokinetics. Rockville (MD): Pharmacometric Press, 1985.Google Scholar
  19. 19.
    Collart P, Poitevin M, Milovanovic A, et al. Kinetic, study of, serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people. Br J Vener Dis. 1980; 56: 355–62.PubMedGoogle Scholar
  20. 20.
    Douglas J, Bax R, Munro J. The pharmacokinetics of cefuroxime in the elderly. J Antimicrob Chemother. 1980; 6: 543–9.PubMedGoogle Scholar
  21. 21.
    Phillips S, Bararaman-Phillips J. The use of intramuscular cefoperazone versus intramuscular ceftriaxone in patients with nursing-home acquired pneumonia. J Am Geriatr Soc. 1993; 4: 1071–4.Google Scholar
  22. 22.
    Shock N, Watkin D, Yiengst B, et al. Age differences in water content of the body as related to basal oxygen consumption in males. J Gerontol. 1963; 18: 1–8.PubMedGoogle Scholar
  23. 23.
    Forbes G, Reina J. Adult lean body mass declines with age: some longitudinal observations. Metabolism. 1970; 19: 653–63.PubMedGoogle Scholar
  24. 24.
    Adelman L, Liebman J. Anatomy of body water and electrolytes. Am J Med. 1959; 27: 256–77.Google Scholar
  25. 25.
    Lowenthal D. Clinical pharmacology. In: Abrams W, Berkow R, editor. Merck manual of geriatrics. Rahway (NJ): Merck & Co Inc, 1990.Google Scholar
  26. 26.
    Lakatta E. Age-related alteration in the cardiovascular response to adrenergic-mediated stress. Fed Proc. 1980; 39: 3173–7.PubMedGoogle Scholar
  27. 27.
    Campion EW, deLabry LO, Glynn RJ. The effect of age on serum albumin in healthy males: report from the normative aging study. J Gerontol. 1988; 43(1): M18–20.PubMedGoogle Scholar
  28. 28.
    Schmucker D. Aging and drug disposition: an update. Pharmacol Rev. 1985; 37: 133–48.PubMedGoogle Scholar
  29. 29.
    Wallace S, Whiting B. Factors affecting drug binding in plasma of elderly patients. Br J Clin Pharmacol. 1976; 3: 327–30.PubMedGoogle Scholar
  30. 30.
    Paxton J. Alpha 1 acid glycoprotein and binding of basic drugs. Methods Find Exp Clin Pharmacol. 1983; 5: 635.PubMedGoogle Scholar
  31. 31.
    Piafsky K. Disease induced changes in the plasma binding of basic drugs. Clin Pharmacokinet. 1980; 5: 246–62.PubMedGoogle Scholar
  32. 32.
    O’Malley K, Crooks J, Duke E, et al. Effects of age and sex on human drug metabolism. BMJ. 1971; 3: 607–9.PubMedGoogle Scholar
  33. 33.
    Vestal R, Wood A, Branch R, et al. Effect of age and cigarette smoking on propranolol disposition. Clin Pharmacol Ther. 1979; 26: 8–15.PubMedGoogle Scholar
  34. 34.
    Bach B, Hansen J, Kampmann J, et al. Disposition of antipyrine and phenytoin correlated with age and liver volume in men. Clin Pharmacokinet. 1981; 6: 389–96.PubMedGoogle Scholar
  35. 35.
    Crooks J, Stephenson I. Drugs and the elderly. London: Macmillan, 1979.Google Scholar
  36. 36.
    Sotaniemi EA, Arranto AJ, Pelkonen O, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1996; 61(3): 331–9.Google Scholar
  37. 37.
    Schmucker DL, Woodhouse KW, Wang RK, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther. 1990; 48(4): 365–74.PubMedGoogle Scholar
  38. 38.
    Yuen G. Altered pharmacokinetics in the elderly. Clin Geriatr Med. 1990; 6: 257–67.PubMedGoogle Scholar
  39. 39.
    Divoll M, Abernethy D, Ameer B, et al. Acetaminophen kinetics in the elderly. Clin Pharmacol Ther. 1982; 31: 151–6.PubMedGoogle Scholar
  40. 40.
    Abernethy D, Greenblatt D, Shader R. Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther. 1985; 232: 183–8.PubMedGoogle Scholar
  41. 41.
    Wood A, Vestal R, Wilkinson G, et al. The effect of aging and cigarette smoking on the elimination of antipyrine and indocyanine green elimination. Clin Pharmacol Ther. 1979; 26: 16–20.PubMedGoogle Scholar
  42. 42.
    Twun-Barima Y, Finnigan T, Habash A, et al. Impaired enzyme induction by rifampicin in the elderly [letter]. Br J Clin Pharmacol. 1984; 17: 595–7.Google Scholar
  43. 43.
    Davies D, Shock N. Age changes in glomerular filtration rates, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest. 1950; 29: 496–507.PubMedGoogle Scholar
  44. 44.
    Rowe J, Andres R, Tobin J, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976; 31: 155–63.PubMedGoogle Scholar
  45. 45.
    Landahl S, Aurell M, Jagenburg R. Glomerular filtration rate at the age of 70 and 75. J Clin Exp Gerant. 1982; 3: 29–45.Google Scholar
  46. 46.
    Watkin D, Shock N. Agewise standard value for Cin, Cpah and Tmpah in adult males. J Clin Invest. 1955; 34: 965.Google Scholar
  47. 47.
    Trollfors B, Norrby R. Estimation of glomerular filtration rate by serum creatinine and serum beta-2-microglobulin. Nephron. 1981; 28: 196–9.PubMedGoogle Scholar
  48. 48.
    Kim K, Onesti G, Ramirez O, et al. Creatinine clearance in renal disease: a reappraisal. BMJ. 1969; 4: 11–4.PubMedGoogle Scholar
  49. 49.
    Cockroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.Google Scholar
  50. 50.
    Baum C, Kennedy D, Forbes M. Utilization of nonsteroidal antiinflamatory drugs. Arthritis Rheum. 1985; 28: 686–92.PubMedGoogle Scholar
  51. 51.
    Taha A, Lenton R, Murdoch P, et al. Non-oliguric renal failure during treatment with mefenamic acid in elderly patients: a continuing problem. Br Med J Clin Res Ed. 1985; 291: 661–2.PubMedGoogle Scholar
  52. 52.
    Unworth J, Sturman S, Lunec J, et al. Renal impairment associated with nonsteroidal antiinflamatory drugs. Ann Rheum Dis. 1987; 46: 233–6.Google Scholar
  53. 53.
    Ciabattoni G, Cinotti G, Pierucci A, et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease. N Engl J Med. 1984; 310: 279–83.PubMedGoogle Scholar
  54. 54.
    Murray M, Brater D. Nonsteroidal antiinflammatory drugs. Clin Geriatr Med. 1990; 6: 365–97.PubMedGoogle Scholar
  55. 55.
    Cornoni-Huntley J, Brock D, Ostfeldt A, et al. Established populations for epidemiologic studies of the elderly. Resource data book [publication no. 86]. Washington, DC: US Government Printing Office, 1986: 2443.Google Scholar
  56. 56.
    Feely J, Coakley D. Altered pharmacodynamics in the elderly. Clin Geriatr Med. 1990; 6(2): 269–83.PubMedGoogle Scholar
  57. 57.
    Lippa AS PR, Beer B, Critchet DJ, et al. Brain cholinergic dysfunction and memory in aged rats. Neurobiol Aging. 1980; 1: 13–9.PubMedGoogle Scholar
  58. 58.
    Abrass IB, Davis JL, Scarpace PJ. Isoproterenol responsiveness and myocardial beta-adrenergic receptors in young and old rats. J Gerontol. 1982; 37(2): 156–60.PubMedGoogle Scholar
  59. 59.
    Roth G, Hess G. Changes in the mechanisms of hormone neurotransmitter action during aging. Current status of the role of receptor and postreceptor alterations: a review. Mech Ageing Dev. 1982; 20: 175–94.PubMedGoogle Scholar
  60. 60.
    Guarnieri T, Filburn CR, Zitnik G, et al. Contractile and biochemical correlates of beta-adrenergic stimulation of the aged heart. Am J Physiol. 1980; 239(4): H501–8.PubMedGoogle Scholar
  61. 61.
    Shimazu T, Takeda A, Fukushima Y. Neural-metabolic interaction in the liver during aging in rats. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier, 1986: 171–81.Google Scholar
  62. 62.
    Borst S, Scarpace P. Reduced high-affinity alpha 1-adrenoceptors in liver of senescent rats: implications of assessment at various temperatures. Br J Pharmacol. 1990; 101: 650–4.PubMedGoogle Scholar
  63. 63.
    Morley J, Flood J, Silver A. Opioid peptides and aging. Ann NY Acad Sci. 1990; 579: 123–32.PubMedGoogle Scholar
  64. 64.
    Roth G. Mechanisms of altered hormone-neurotransmitter action during aging: from receptors to calcium mobilization. Ann Rev Gerontol Geriatr. 1990; 10: 132–46.Google Scholar
  65. 65.
    Peterson C. Changes in calcium’s role as messenger during aging in neuronal and nonneuronal cells. Ann NY Acad Sci. 1992; 663: 279–93.PubMedGoogle Scholar
  66. 66.
    Castleden CM, George CF, Marcer D, et al. Increased sensitivity to nitrazepam in old age. BMJ. 1977; I: 10–12.Google Scholar
  67. 67.
    Larsson E, Kukull W, Buchner D, et al. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med. 1987; 107: 169–73.Google Scholar
  68. 68.
    Bender A. Pharmacologic aspects of aging: a survey of the effect of age on drug activity in adults. J Am Geriatr Soc. 1964; 12: 114–34.PubMedGoogle Scholar
  69. 69.
    Kallman H. Depression in the elderly. Compendium of three years of clinical use. Proceedings of Symposium on Desyrel®. 1984 Sep 14; Evansville (IL): Mead-Johnson Pharmaceut Division, 1985: 31–40.Google Scholar
  70. 70.
    Gribbin B, Pickering T, Sleight P, et al. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res. 1971; 29: 424–31.PubMedGoogle Scholar
  71. 71.
    McGarry K, Laher M, Fitzgerald D, et al. Baroreflex function in elderly hypertensives. Hypertension. 1975; 5: 763–6.Google Scholar
  72. 72.
    Schatz I. Orthostatic hypotension: I. Functional and neurogenic causes. Arch Intern Med. 1984; 144: 773–7.PubMedGoogle Scholar
  73. 73.
    Schatz I. Orthostatic hypotension: II. Clinical diagnosis, testing and treatment. Arch Intern Med. 1984; 144: 1037–41.PubMedGoogle Scholar
  74. 74.
    Come P, Pitt B. Nitroglycerin-induced severe hypotension and bradycardia in patients with acute myocardial infarction. Circulation. 1976; 54: 624–8.PubMedGoogle Scholar
  75. 75.
    Alpert J. Nitrate therapy in the elderly. Am J Cardiol. 1990; 65: 23J–7J.PubMedGoogle Scholar
  76. 76.
    Weidmann P, De Myttenaere-Bursztein S, Maxwell M, et al. Effect of aging on plasma renin and aldosterone in normal man. Kidney Int. 1975; 8: 325–33.PubMedGoogle Scholar
  77. 77.
    Epstein M, Hollenberg N. Age as a determinant of renal sodium conservation in normal man. J Lab Clin Med. 1976; 87: 411–7.PubMedGoogle Scholar
  78. 78.
    Buhler F, Hulthen U, Kiowski W, et al. The place of the calcium antagonist verapamil in antihypertensive therapy. J Cardiovasc Pharmacol. 1982; 4 Suppl. 3: 5350–7.Google Scholar
  79. 79.
    Shannon R, Minaker K, Rowe J. Aging and water balance in humans. Semin Nephrol. 1984; 4: 346–53.Google Scholar
  80. 80.
    Rowe J, Shock N, deFronzo R. The influence of age on the renal response to water deprivation in man. Nephron. 1976; 17: 270–8.PubMedGoogle Scholar
  81. 81.
    Lindeman R, Lee Jr T, Yiengst M, et al. Influence of age, renal disease, hypertension, diuretics and calcium on the antidiuretic response to suboptimal infusions of vasopressin. J Lab Clin Med. 1966; 68: 206–23.PubMedGoogle Scholar
  82. 82.
    Rowe S, Minaker K, Sparrow D, et al. Age-related failure of volume-pressure-mediated vasopressin release. J Clin Endocrinol. 1982; 54: 661–4.Google Scholar
  83. 83.
    Geller J. Benign prostatic hyperplasia: pathogenesis and medical therapy. J Am Geriatr Soc. 1993; 39: 1208–16.Google Scholar
  84. 84.
    Crooks J. Aging and drug disposition: pharmacodynamics. J Chronic Dis. 1983; 36(1): 85–90.PubMedGoogle Scholar
  85. 85.
    Davies KN, Castleden CM. Ageing and receptors. In: Grimley-Evans J, Caird FI, editors. Advanced geriatric medicine. London: Wright, 1988.Google Scholar
  86. 86.
    Ziegler MG, Lake CR, Kopin IJ. Plasma noradrenaline increases with age. Nature. 1976; 261(5558): 333–5.PubMedGoogle Scholar
  87. 87.
    Pan H, Hoffmann B, Pershe R, et al. Decline in beta-adrenergic receptor-mediated relaxation with aging in man. J Pharmacol Exp Ther. 1986; 239: 802–7.PubMedGoogle Scholar
  88. 88.
    Ford G, Hoffmann B, Vestal R, et al. Age-related changes in adenosine and beta-adrenergic responsiveness of vascular smooth muscle in man. Br J Clin Pharmacol. 1992; 33: 83–8.PubMedGoogle Scholar
  89. 89.
    Hiremath A, Pershe R, Hoffmann B, et al. Comparison of agerelated changes in prostaglandin Ei and beta-adrenergic responsiveness of vascular smooth muscle in adult males. J Gerontol. 1989; 44: M13–7.PubMedGoogle Scholar
  90. 90.
    Brummelen P, Buhler F, Kiowski W, et al. Age-related decrease in cardiac and peripheral vascular responsiveness to isoprenaline: studies in normal subjects. Clin Sci. 1981; 60: 571–7.PubMedGoogle Scholar
  91. 91.
    Ford GA, James OFW. Effect of autonomic blockade on cardiac beta-adrenergic chronotropic pesponsiveness in healthy young, healthy elderly and endurance-trained elderly subjects. Clin Sci. 1994; 87: 297–302.PubMedGoogle Scholar
  92. 92.
    Abrass IB, Scarpace PJ. Catalytic unit of adenylate cyclase: reduced activity in aged-human lymphocytes. J Clin Endocrinol Metab. 1982; 55(5): 1026–8.PubMedGoogle Scholar
  93. 93.
    Scarpace PJ. Decreased receptor activation with age: can it be explained by desensitization? J Am Geriatr Soc. 1988; 36(11): 1067–71.PubMedGoogle Scholar
  94. 94.
    Conolly MJ. Aging, late-onset asthma and the beta-adrenoceptor. Pharmacol Ther. 1993; 60(3): 389–404.Google Scholar
  95. 95.
    Brawn LA, Castleden CM. Adverse drug reactions: an overview of special considerations in the management of the elderly patient. Drug Saf. 1990; 5(6): 421–35.PubMedGoogle Scholar
  96. 96.
    Conolly M, Crowley J, Nielson C, et al. Peripheral mononuclear leucocyte beta-adrenoceptor and non-specific bronchial responsiveness to methacholine in young and elderly normal subjects and asthmatic patients. Thorax. 1994; 49: 26–32.Google Scholar
  97. 97.
    Feldmann R, Limbild L, Nadeau J, et al. Alterations in leukocyte beta-receptor affinity with aging: a potential explanation for altered beta-adrenergic sensitivity in the elderly. N Engl J Med. 1984; 310: 815–9.Google Scholar
  98. 98.
    Sowinski K, Forrest A, Wilton J, et al. Effect of aging on atelonol pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 1995; 35(8): 807–14.PubMedGoogle Scholar
  99. 99.
    Elliot H. Calcium antagonists in the treatment of hypertension and angina pectoris in the elderly. J Cardiovasc Pharmacol. 1989; 13 Suppl. 4: S12–S16.Google Scholar
  100. 100.
    Schwartz J, Troconiz I, Verotta D, et al. Aging effects on stereoselective pharmacokinetics and pharmacodynamics of verapamil. J Pharmacol Exp Ther. 1993; 265(2): 690–8.PubMedGoogle Scholar
  101. 101.
    Robertson D, Waller A, Renwick C, et al. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. Br J Clin Pharmacol. 1988; 25(3): 297–305.PubMedGoogle Scholar
  102. 102.
    Donnelly R, Elliott H. Factors influencing the response to calcium antagonists in elderly patients with hypertension and ischaemic heart disease. Exp Gerontol 1990; 25 (3–4): 375–81.PubMedGoogle Scholar
  103. 103.
    Lettieri J, Krol G, Yeh S, et al. The effects of age and race on nitrendipine pharmacokinetics and pharmacodynamics. J Cardiovasc Pharmacol. 1988; 12 Suppl. 4: S129–32.PubMedGoogle Scholar
  104. 104.
    Macdonald N, Sioufi A, Howie C, et al. The effect of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril. Br J Clin Pharmacol. 1993; 36(3): 205–9.PubMedGoogle Scholar
  105. 105.
    Andros E, Detmar-Hanna D, Suteparuk S, et al. The effect of aging on the pharmacokinetics and pharmacodynamics of prazosin. Eur J Clin Pharmacol 1996; 50 (1–2): 41–6.PubMedGoogle Scholar
  106. 106.
    Kelly J, O’Malley K. Nitrates in the elderly: pharmacological considerations. Drugs Aging. 1992; 2(1): 14–9.PubMedGoogle Scholar
  107. 107.
    Tsang P, Gerson B. Understanding digoxin use in the elderly patient. Clin Lab Med. 1990; 10(3): 479–92.PubMedGoogle Scholar
  108. 108.
    Mooradian A. Digitalis: an uptake of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet. 1988; 15: 165–79.PubMedGoogle Scholar
  109. 109.
    Kennedy R, Seilen E. Ouabain-sensitive 86Rb+ uptake rate and responsiveness to digoxin in rat left atrial muscle. J Pharmacol Exp Ther. 1989; 248: 104–10.PubMedGoogle Scholar
  110. 110.
    Ruiz J, Array S, Lowenthal D. Therapeutic drug monitoring in the elderly. Am J Ther. 1996; 3: 839–60.PubMedGoogle Scholar
  111. 111.
    Shepherd AM, Hewick DS, Moreland TA, et al. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977; 4(3): 315–20.PubMedGoogle Scholar
  112. 112.
    Husted S, Andreasen F. The influence of age on the response to anticoagulants. Br J Clin Pharmacol. 1977; 4(5): 559–65.PubMedGoogle Scholar
  113. 113.
    O’Malley K, Kelly J, Swift C. Responsiveness to drugs. In: Swift C, editor. Clinical pharmacology in the elderly. New York: Marcel Dekker, 1987: 83–101.Google Scholar
  114. 114.
    Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA. 1989; 262: 3303–7.PubMedGoogle Scholar
  115. 115.
    Greenblatt DJ, Allen MD. Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program. Br J Clin Pharmacol. 1978; 5(5): 407–13.PubMedGoogle Scholar
  116. 116.
    Hewick DS, Shaw V. Tissue distribution of radioactivity after injection of [14C]nitrazepam in young and old rats. J Pharm Pharmacol. 1978; 30(5): 318–9.PubMedGoogle Scholar
  117. 117.
    Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther. 1980; 27(3): 301–12.PubMedGoogle Scholar
  118. 118.
    Reidenberg M, Levy M, Warner H. Relationship between diazepam ldose, plasma level, age, and central nervous system depression. Clin Pharmacol Ther. 1978; 23: 371–4.PubMedGoogle Scholar
  119. 119.
    Cook PJ, Flanagan R, James IM. Diazepam tolerance: effect of age, regular sedation, and alcohol. Br Med J Clin Res Ed. 1984; 289(6441): 351–3.PubMedGoogle Scholar
  120. 120.
    Greenblatt D, Ehrenberg B, Scavone J, et al. Increased sensitivity to midazolam in the elderly. Clin Pharmacol Ther. 1990; 47: 210.Google Scholar
  121. 121.
    Kanto J, Kangas L, Aaltonen L, et al. Effect of age on the pharmacokinetics and sedative effect of flunitrazepam. J Clin Pharmacol. 1981; 19: 400–4.Google Scholar
  122. 122.
    Memo M, Spano PF, Trabucchi M. Brain benzodiazepine receptor changes during ageing [letter]. J Pharm Pharmacol. 1981; 33(1): 64.PubMedGoogle Scholar
  123. 123.
    Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet. 1995; 29(3): 192–209.PubMedGoogle Scholar
  124. 124.
    Ozdemir V, Fourie J, Busto U, et al. Pharmacokinetic changes in the elderly: do they contribute to drug abuse and dependence? Clin Pharmacokinet. 1996; 31(5): 372–85.PubMedGoogle Scholar
  125. 125.
    Rochon PA, Gurwitz JH. Drug therapy. Lancet. 1995; 346(8966): 32–6.PubMedGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Andrea Hämmerlein
    • 1
  • Hartmut Derendorf
    • 1
  • David T. Lowenthal
    • 2
    • 3
  1. 1.Department of PharmaceuticsUniversity of FloridaGainesvilleUSA
  2. 2.Department of MedicineUniversity of FloridaGainesvilleUSA
  3. 3.Geriatric Research, Education and Clinical CenterVA Medical CenterGainesvilleUSA

Personalised recommendations