Clinical Pharmacokinetics

, Volume 1, Issue 4, pp 280–296 | Cite as

Pharmacokinetics in the Elderly

  • J. Crooks
  • K. O’Malley
  • I. H. Stevenson
Article

Summary

The elderly are generally considered to be different from young people in terms of drug response and this applies particularly to quantitative differences. While altered drug handling is a major potential source of difference in responsiveness to drugs, the relative contribution of pharmacokinetics and pharmacodynamics to this difference is not clear. In the present review we have examined the available data on pharmacokinetics in the elderly.

In the past, data pertaining to animal models have been extrapolated to man and in the absence of human experimentation these assumptions have tended to hold sway. This is best exemplified by studies on drug absorption. The absorption of actively transported substances may in fact be diminished in the elderly. However, most drugs are absorbed by passive diffusion and the recently available evidence in man indicates that there is no age-dependent change.

While definitive data on the effect of old age on drug metabolising ability in animals is available, no direct assessments have been made in man. Many of the studies carried out using drug plasma half-life and clearance assessments are complicated by changes in distribution. This is best illustrated by a definitive study with diazepam, in which marked prolongation of plasma half-life was accompanied by an increase in apparent volume of distribution in the elderly. This latter change influences plasma drug clearance and, possibly, drug concentration at its site of action. Thus, the implications for drug effect of such changes in volume of distribution remain to be clarified.

In theory, the rate of elimination of antipyrine should provide a good index of drug metabolising ability. Both plasma half-life and clearance values suggest a decrease in metabolism in the elderly. No other drug has been studied as intensively and the evidence for a diminished metabolism of other drugs in the elderly is less definite. Thus, while it is likely that the metabolism of some drugs is impaired in old age, it is not possible at this time to generalise with regard to the effect of age on drug metabolising ability in man.

It is also difficult to generalise about age-related changes in plasma protein binding of drugs. With some drugs, binding to plasma protein does not appear to be altered and for two drugs — warfarin and phenytoin, the findings of different investigators conflict.

Diminution of glomerular filtration rate, renal plasma flow and associated tubular function with age have been well documented. Drug clearance comparisons between old and young have been carried out for only three renally excreted drugs — digoxin, propicillin and sulphamethizole. With digoxin and sulphamethizole, the evidence is that renal excretion is diminished in the elderly. With propicillin, changes in volume of distribution predominate, resulting in higher plasma levels in the elderly but similar percent recovery in urine. In the remaining studies, drug plasma levels and/or plasma half-life values indicate that older patients are exposed to higher plasma concentrations of drugs and while the data is insufficient to explain the findings in kinetic terms, it is likely that diminished renal excretion is mainly responsible.

In conclusion, with the exception of renally-excreted drugs, there is at present insufficient data on which to make recommendations with respect to doses of drugs in the elderly. The importance of changes in volume of distribution are not clear and data obtained from single dose studies are not necessarily pertinent to multiple dose continuous therapy. In addition, many elderly patients have multiple pathology and the findings from studies on healthy subjects may not be applicable. Future studies must combine pharmacokinetic and pharmacodynamic aspects in the relevant clinical setting so that the practical significance, if any, of altered kinetics emerges.

Keywords

Warfarin Digoxin Renal Excretion Plasma Protein Binding Antipyrine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bender, A.D.: Effect of increasing age on the distribution of peripheral blood flow in man. Journal of the American Geriatric Society 13: 192–198 (1965).Google Scholar
  2. Bender, A.D.: Effect of age on intestinal absorption: Implications for drug absorption in the elderly. Journal of the American Geriatric Society 16: 1331–1339 (1968).Google Scholar
  3. Bender, A.D.: Geriatric pharmacology. Age and its influence on drug action in adults. Drug Information Bulletin 3: 153–158 (1969).Google Scholar
  4. Bender, A.D.; Post, A.; Meier, J.P.; Higson, J.E. and Reichard G.: Plasma protein binding of drugs as a function of age in adult human subjects. Journal of Pharmaceutical Sciences 64: 1711–1713 (1975).PubMedCrossRefGoogle Scholar
  5. Branch, R.A.; Shand, D.G.; Wilkinson, G.R. and Nies, A.S.: Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Journal of Clinical Investigation 53: 1101–1107 (1974).PubMedCrossRefGoogle Scholar
  6. Briant, R.H.; Liddle, D.E.; Dorrington, R. and Williams F.M.: Plasma half-life of two analgesic drugs in young and elderly adults. New Zealand Medical Journal 82: 136–137 (1975).Google Scholar
  7. Bromage, P.R.: Exaggerated spread of epidural analgesia in arteriosclerotic patients. British Medical Journal 2: 1634–1638 (1962).PubMedCrossRefGoogle Scholar
  8. Castleden, C.M.; Kaye, C.M. and Parsons, R.L.: The effect of age on plasma levels of propranolol and practolol in man. British Journal of Clinical Pharmacology 2: 303–306 (1975).PubMedCrossRefGoogle Scholar
  9. Chan, K.; Kendall, M.J.; Mitchard, M.; Wells, W.D.E. and Vickers, M.D.: The effect of aging on plasma pethidine concentration. British Journal of Clinical Pharmacology 2: 297–302 (1975).PubMedCrossRefGoogle Scholar
  10. Davies, D.F. and Shock, N.W.: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. Journal of Clinical Investigation 29: 496–507 (1950).PubMedCrossRefGoogle Scholar
  11. Edelman, I.S. and Leibman, J.: Anatomy of body water and electrolytes. American Journal of Medicine 27: 256–277 (1959).PubMedCrossRefGoogle Scholar
  12. Ehrnebo, M.; Agurell, S.; Boreus, L.O.; Gordon, E. and Lonroth U.: Pentazocine binding to blood cells and plasma proteins. Clinical Pharmacology and Therapeutics 16: 424–429 (1974).PubMedGoogle Scholar
  13. Ewy, G.A.; Kapadia, G.G.; Yao, L.; Lullin, M. and Marcus F.I.: Digoxin metabolism in the elderly. Circulation 39: 449–453 (1969).PubMedCrossRefGoogle Scholar
  14. Gorrod, J.W.: Absorption, metabolism and excretion of drugs in geriatric subjects. Gerontologia Clinica 16: 30–42 (1974).CrossRefGoogle Scholar
  15. Hayes, M.J.; Langman, M.J.S. and Short A.H.: Changes in drug metabolism with increasing age. 1. Warfarin binding and plasma proteins. British Journal of Clinical Pharmacology 2: 69–72 (1975a).PubMedGoogle Scholar
  16. Hayes, M.J.; Langman, M.J.S. and Short A.H.: Changes in drug metabolism with increasing age. 2. Phenytoin clearance and protein binding. British Journal of Clinical Pharmacology 2: 73–79 (1975b).PubMedGoogle Scholar
  17. Hewick, D.S.; Moreland, T.A.; Shepherd, A.M.M. and Stevenson I.H.: The effect of age on the sensitivity to warfarin sodium. British Journal of Clinical Pharmacology 2: 189P–190P (1975).Google Scholar
  18. Hooper, W.D.; Bochner, F.; Eadie M.J. and Tyrer, J.H.: Plasma protein binding of diphenylhydantoin: Effects of sex hormones, renal and hepatic disease. Clinical Pharmacology and Therapeutics 15: 276–282 (1974).PubMedGoogle Scholar
  19. Houghton, G.W.; Richens, A. and Leighton, M.: Effects of age, height, weight and sex on serum phenytoin concentration in epileptic patients. British Journal of Clinical Pharmacology 2: 251–256 (1975).PubMedCrossRefGoogle Scholar
  20. Irvíne, R.E.; Grove, J.; Toseland, P.A. and Trounce, J.R.: The effect of age on the hydroxylation of amylobarbitone sodium in man. British Journal of Clinical Pharmacology 1: 41–43 (1974).PubMedCrossRefGoogle Scholar
  21. Jori, A.; Di Salle, E. and Quadri A. Rate of aminopyrine disappearance from plasma in young and aged humans. Pharmacology 8: 273–279 (1972).PubMedCrossRefGoogle Scholar
  22. Kato, R.; Chiesara, E. and Frontino, G.: Influence of sex difference on the pharmacological action and metabolism of some drugs. Biochemical Pharmacology 11: 221–227 (1962).PubMedCrossRefGoogle Scholar
  23. Kato, R. and Takanaka, A.: Effect of phenobarbital on electron transport system, oxidation and reduction of drugs in liver microsomes of rats of different age. Journal of Biochemistry (Tokyo) 63: 406–408 (1968).Google Scholar
  24. Kato, R.; Vassanelli, P.; Frontino, G. and Chiesara, E.: Variation in the activity of liver microsomal drug-metabolising enzymes in rats in relation to age. Biochemical Pharmacology 13: 1037–1051 (1964).PubMedCrossRefGoogle Scholar
  25. Klotz, U.: Pathophysiological and disease-induced changes in drug distribution volume: Pharmacokinetic implications. Clinical Pharmacokinetics 1: 204–218 (1976).PubMedCrossRefGoogle Scholar
  26. Klotz, U.; Avant, G.R.; Hoyumpa, A.; Schenker S. and Wilkinson, G.R.: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. Journal of Clinical Investigation 55: 347–359 (1975).PubMedCrossRefGoogle Scholar
  27. Kristensen, M.; Molholm Hansen, J.; Kampmann, J.; Lumholtz, B. and Siersback-Nielsen, K.: Drug elimination and renal function. Journal of Clinical Pharmacology 14: 307–308 (1974).PubMedGoogle Scholar
  28. Leikola, E. and Vartia, K.O.: On penicillin levels in young and geriatric subjects. Journal of Gerontology 12: 48–52 (1957).PubMedCrossRefGoogle Scholar
  29. Mather, L.E.; Tucker, G.T.; Pflug, A.E.; Lindop, M.J. and Wilkerson, C.: Meperidine kinetics in man: Intravenous injection in surgical patients and volunteers. Clinical Pharmacology and Therapeutics 17: 21–30 (1975).PubMedGoogle Scholar
  30. Miller, J.H.; McDonald, R.K. and Shock, N.W.: Age changes in the maximal rate of renal tubular reabsorption of glucose. Journal of Gerontology 7: 196–200 (1952).PubMedCrossRefGoogle Scholar
  31. Molholm-Hansen, J.; Kampmann J. and Laursen, H.: Renal excretion of drugs in the elderly. Lancet 1: 1170 (1970).CrossRefGoogle Scholar
  32. Nies, A.S.; Shand, D.G. and Wilkinson, G.R.: Altered hepatic blood flow and drug disposition. Clinical Pharmacokinetics 1: 135–155 (1976).PubMedCrossRefGoogle Scholar
  33. Novak, L.P.: Aging, total body potassium, fat free mass and cell mass in males and females between the ages 18 and 85 years. Journal of Gerontology 27: 438–443 (1972).PubMedCrossRefGoogle Scholar
  34. O’Malley, K.; Crooks, J.; Duke, E. and Stevenson I.H.: Effect of age and sex on human drug metabolism, British Medical Journal 3: 607–609 (1971).PubMedCrossRefGoogle Scholar
  35. O’Malley, K.: Ph.D. Thesis, University of Dundee (1973).Google Scholar
  36. O’Malley, K.; Judge, T. and Crooks, J.: Geriatric clinical pharmacology and therapeutics; in Avery (Ed) Drug Treatment p 122–142 (ADIS Press, Sydney 1976).Google Scholar
  37. Rowland, M.; Benet, L.Z. and Graham, G.G.: Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1: 123–136 (1973).PubMedGoogle Scholar
  38. Shepherd, A.M.M.; Hewick, D.S.; Moreland, T.A. and Stevenson, I.H.: The effect of age on sensitivity to warfarin. British Journal of Clinical Pharmacology. In press (1976).Google Scholar
  39. Shock, N.W.: Age changes in renal function; in Lansing (Ed) Cowdreys Problems of Ageing, p. 614–630 (Williams & Wilkins, Baltimore 1952).Google Scholar
  40. Simon, C.; Malerczyk, V.; Muller, U. and Muller, G.: Zur Pharmakokinetik von propicillin bei geriatrischen Patienten im vergleich zu jungeren erwachsenen. Deutsche medizinische Wochenschrift 97: 1999–2003 (1972).PubMedCrossRefGoogle Scholar
  41. Traeger, A.; Kunze, M.; Stein, G. and Ankermann, H.: Zur Pharmakokinetik von Indomethazin bei alten Menschen. Z. Alternsforsch. 27: 151–155 (1973).Google Scholar
  42. Traeger, A.; Kiesewetter, R. and Kunze, M.: Zur Pharmakokinetik von Phenobarbital Bei Erwachsenen und Greisen. Dtsch. Ges. Wesen. 29: 1040–1042 (1974).Google Scholar
  43. Triggs, E.J.; Nation, R.L.; Long, A. and Ashley, J.J.: Pharmacokinetics in the elderly. European Journal of Clinical Pharmacology 8: 55–62 (1975).PubMedCrossRefGoogle Scholar
  44. Triggs, E.J. and Nation, R.L.: Pharmacokinetics in the aged: A review. Journal of Pharmacokinetics and Biopharmaceutics 3: 387–418 (1975).PubMedGoogle Scholar
  45. Vestal., R.E.; Norris, A.H.; Tobin, J.D.; Cohen, B.H.; Shock, N.W. and Andres, R.: Antipyrine metabolism in man: influence of age, alcohol, caffeine, and smoking. Clinical Pharmacology and Therapeutics 18: 425–432 (1975).PubMedGoogle Scholar
  46. Vartia, K.O. and Leikola, E.: Serum levels of antibiotics in young and old subjects following administrations of dihydrostreptomycin and tetracycline. Journal of Gerontology 15: 392–394 (1960).PubMedCrossRefGoogle Scholar
  47. Wallace, S.; Whiting B. and Runcie J.: Factors affecting drug binding in plasma of elderly patients. British Journal of Clinical Pharmacology 3: 327–330 (1976).PubMedCrossRefGoogle Scholar
  48. Woodford-Williams, E.; Alvares, A.S.; Webster, D.; Landless, B. and Dixon, M.P.: Serum protein patterns in ‘normal’ and pathological ageing. Gerontologia 10: 86–99 (1964).CrossRefGoogle Scholar

Copyright information

© ADIS Press 1976

Authors and Affiliations

  • J. Crooks
    • 1
  • K. O’Malley
    • 1
  • I. H. Stevenson
    • 1
  1. 1.Department of Pharmacology and Therapeutics, Ninewells HospitalUniversity of DundeeDundeeScotland

Personalised recommendations