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Anticonvulsant Therapy in Aged Patients

Clinical Pharmacokinetic Considerations

  • Clinical Pharmacology
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Summary

Alterations in drug disposition that occur with aging are now becoming widely recognised, and there is an increasing number of drugs for which the approach to therapy in elderly patients can be based on pharmacokinetic data. Both healthy aging and comorbid disease can alter the responsiveness of the body to drugs and to their absorption, distribution and elimination.

Altered absorption in the elderly has not been documented after oral ingestion of any anticonvulsant drug. Increased adipose tissue in the elderly may raise the apparent volume of distribution (Vd) of lipid-soluble drugs. An increased Vd in the elderly has been shown for diazepam and clobazam, but not midazolam. The data are inconclusive for phenytoin and valproic acid (sodium valproate). The decreased plasma protein binding that often occurs in the elderly has few clinical consequences. The reduced liver function that tends to occur with aging seems to affect the elimination of drugs that are mainly cleared by oxidative metabolism [e.g. carbamazepine, phenytoin and phenobarbital (phenobarbitone)]. Reduced clearances for methylphenobarbital (methylphenobarbitone), diazepam, midazolam and clobazam occur in elderly men, but not in women. The reduced renal function that is seen in old age affects the disposition of drugs that are eliminated mainly by direct renal excretion. Thus, the clearances of vigabatrin and gabapentin correlate with creatinine clearance. Such considerations may help guide anticonvulsant dosage in the elderly.

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References

  1. Scheuer ML, Cohen J. Seizures and epilepsy in the elderly. Neurol Clin 1993; 11(4): 787–804

    PubMed  CAS  Google Scholar 

  2. Hauser WA. Seizure disorders: the changes with age. Epilepsia 1992; 33 Suppl.4:S6–14

    Article  PubMed  Google Scholar 

  3. Loiseau J, Loiseau P, Duche B, et al. A survey of epileptic disorders in southwest France: seizures in elderly patients. Ann Neurol 1990; 27(3): 232–7

    Article  PubMed  CAS  Google Scholar 

  4. Tallis R, Hall G, Craig I, et al. How common are epileptic seizures in old age?. Age Ageing 1991; 20: 442–8

    Article  PubMed  CAS  Google Scholar 

  5. Hildick-Smith M. Late-onset epilepsy. Br J Clin Pharmacol 1994; 48(2): 87–90

    CAS  Google Scholar 

  6. Parker BM, Cusack BJ, Vestal RE. Pharmacokinetic optimisation of drug therapy in elderly patients. Drugs Aging 1995; 7: 10–8

    Article  PubMed  Google Scholar 

  7. Willmore LJ. The effect of age on pharmacokinetics of antiepi-leptic drugs. Epilepsia 1995; 36 Suppl. 5: S14–21

    Article  PubMed  Google Scholar 

  8. Leppik IE. Metabolism of antiepileptic medication: newborn to elderly. Epilepsia 1992; 33 Suppl. 4: S32–40

    Article  PubMed  Google Scholar 

  9. Thomson AH, Brodie MJ. Pharmacokinetic optimisation of an-ticonvulsant therapy. Clin Pharmacokinet 1992; 23(3): 216–30

    Article  PubMed  CAS  Google Scholar 

  10. Greenblatt DJ, Shader RI, Harmatz JS. Implications of altered drug disposition in the elderly: studies of benzodiazepines. J Clin Pharmacol 1989; 29: 866–72

    PubMed  CAS  Google Scholar 

  11. Feely J, Coakley D. Altered pharmacodynamics in the elderly. Clin Geriatr Med 1990; 6(2): 269–83

    PubMed  CAS  Google Scholar 

  12. Bender DA. Effect of age on intestinal absorption: implications for drug absorption in the elderly. J Am Geriatr Soc 1968; 16(12): 1331–9

    PubMed  CAS  Google Scholar 

  13. Greenblatt DJ, Abernethy DR, Shader RI. Pharmacokinetic aspects of drug therapy in the elderly. Ther Drug Monit 1986; 8(3): 249–55

    Article  PubMed  CAS  Google Scholar 

  14. Verbeeck RK, Cardinal J-A, Wallace SM. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 1984; 27: 91–7

    PubMed  CAS  Google Scholar 

  15. Greenblatt DJ. Reduced serum albumin concentration in the elderly: a report from the Boston Collaborative Drug Surveillance Program. J Am Geriatr Soc 1979; 27(1): 20–2

    PubMed  CAS  Google Scholar 

  16. Rolan PE. Plasma protein binding displacement interactions -why are they still regarded as clinically important?. Br J Clin Pharmacol 1994; 37: 125–8

    Article  PubMed  CAS  Google Scholar 

  17. Wallace SM, Verbeeck RK. Plasma protein binding of drugs in the elderly. Clin Pharmacokinet 1987; 12: 41–72

    Article  PubMed  CAS  Google Scholar 

  18. Dawling S, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1989; 17(4): 236–63

    Article  PubMed  CAS  Google Scholar 

  19. Cloyd J. Pharmacokinetic pitfalls of present antiepileptic medications. Epilepsia 1991; 32 Suppl. 5: S53–65

    PubMed  Google Scholar 

  20. Durnas C, Loi C-M, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19(5): 359–89

    Article  PubMed  CAS  Google Scholar 

  21. Bach B, Hansen JM, Kampmann JP, et al. Disposition of anti-pyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet 1981; 6: 389–96

    Article  PubMed  CAS  Google Scholar 

  22. Swift CG, Homeida M, Halliwell M, et al. Antipyrine disposition and liver size in the elderly. Eur J Clin Pharmacol 1978; 14: 149–52

    Article  PubMed  CAS  Google Scholar 

  23. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989; 9(2): 297–301

    Article  PubMed  CAS  Google Scholar 

  24. Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. N Engl J Med 1982; 306(18): 1081–8

    Article  PubMed  CAS  Google Scholar 

  25. Greenblatt DJ, Divoll M, Abernethy DR, et al. Antipyrine kinetics in the elderly: prediction of age related changes in benz-odiazepine oxidizing capacity. J Pharmacol Exp Ther 1982; 220: 120–6

    PubMed  CAS  Google Scholar 

  26. Schmucker DL. Aging and drug disposition: an update. Pharmacol Rev 1985; 37(2): 133–48

    PubMed  CAS  Google Scholar 

  27. Friedman SA, Raizner AE, Rosen H, et al. Functional defects in the aging kidney. Ann Intern Med 1972; 76: 41–5

    PubMed  CAS  Google Scholar 

  28. Rowe JW, Andres R, Tobin JD, et al. Age-adjusted standards for creatinine clearance. Ann Intern Med 1976; 84(5): 567–9

    PubMed  CAS  Google Scholar 

  29. Cloyd JC, Lackner TE, Leppik IE. Antiepileptics in the elderly: pharmacoepidemiology and pharmacokinetics. Arch Fam Med 1994; 3: 589–98

    Article  PubMed  CAS  Google Scholar 

  30. Hockings N, Pall A, Moody J, et al. The effects of age on carba-mazepine pharmacokinetics and adverse effects. Br J Clin Pharmacol 1986; 22: 725–8

    Article  PubMed  CAS  Google Scholar 

  31. Scheuer ML, McCullough K. Carbamazepine clearance in the elderly [abstract]. Neurology 1995; 45 Suppl. 4: 360

    Google Scholar 

  32. Hooper WD, Bochner F, Eadie MJ, et al. Plasma protein binding of diphenylhydantoin: effects of sex hormones, renal and hepatic disease. Clin Pharmacol Ther 1974; 15(3): 276–82

    PubMed  CAS  Google Scholar 

  33. Hayes MJ, Langman MJS, Short AH. Changes in drug metabolism with increasing age: 2. Phenytoin clearance and protein binding. Br J Clin Pharmacol 1975; 2: 73–9

    PubMed  CAS  Google Scholar 

  34. Patterson M, Heazelwood R, Smithurst B, et al. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol 1982; 13: 423–5

    Article  PubMed  CAS  Google Scholar 

  35. Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther 1982; 31: 301–4

    Article  PubMed  CAS  Google Scholar 

  36. Borga O, Hoppel C, Odar-Cederlof I, et al. Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure. Clin Pharmacol Ther 1979; 26(3): 306–13

    PubMed  CAS  Google Scholar 

  37. Davis R, Peters DH, McTavish D. Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994; 47(2): 332–72

    Article  PubMed  CAS  Google Scholar 

  38. Perucca E, Gatti G, Frigo GM, et al. Pharmacokinetics of valproic acid after oral and intravenous administration. Br J Clin Pharmacol 1978; 5: 313–8

    Article  CAS  Google Scholar 

  39. Perucca E, Gatti G, Frigo GM, et al. Disposition of sodium valproate in epileptic patients. Br J Clin Pharmacol 1978; 5: 495–9

    Article  PubMed  CAS  Google Scholar 

  40. Nitsche V, Mascher H. The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia 1982; 23: 153–62

    Article  PubMed  CAS  Google Scholar 

  41. Bryson SM, Verma N, Scott PJW, et al. Pharmacokinetics of valproic acid in young and elderly subjects. Br J Clin Pharmacol 1983; 16: 104–5

    Article  PubMed  CAS  Google Scholar 

  42. Perucca E, Grimaldi R, Gatti G, et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 1984; 17: 665–9

    Article  PubMed  CAS  Google Scholar 

  43. Bauer LA, Davis R, Wilensky A, et al. Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults. Clin Pharmacol Ther 1985; 37(6): 697–700

    Article  PubMed  CAS  Google Scholar 

  44. Cramer JA, Mattson RH. Valproic acid: in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979; 1: 105–16

    Article  PubMed  CAS  Google Scholar 

  45. Dickinson RG, Kluck RM, Hooper WD, et al. Rearrangement of valproate glucuronide in a patient with drug-associated hepatobiliary and renal dysfunction. Epilepsia 1985; 26(6): 589–93

    Article  PubMed  CAS  Google Scholar 

  46. Fenselau C. Acyl glucuronides as chemically reactive intermediates. In: Kauffman FC, editor. Handbook of experimental pharmacology 112: conjugation-deconjugation reactions in drug metabolism and toxicity. Berlin: Springer-Verlag, 1994: 367–85

    Chapter  Google Scholar 

  47. Eadie MJ, Lander CM, Hooper WD, et al. Factors influencing plasma phenobarbitone levels in epileptic patients. Br J Clin Pharmacol 1977; 4: 541–7

    Article  PubMed  CAS  Google Scholar 

  48. Bernus I, Dickinson RG, Hooper WD, et al. Urinary excretion of phenobarbitone and its metabolites in chronically treated patients. Eur J Clin Pharmacol 1994; 46: 473–5

    Article  PubMed  CAS  Google Scholar 

  49. Martines C, Gatti G, Sasso E, et al. The disposition of primidone in elderly patients. Br J Clin Pharmacol 1990; 30: 607–11

    Article  PubMed  CAS  Google Scholar 

  50. Levy RH, Schmidt D. Utility of free level monitoring of anti- epileptic drugs. Epilepsia 1985; 26: 199–205

    Article  PubMed  CAS  Google Scholar 

  51. Eadie MJ, Hooper WD. Other barbiturates: methylphenobarbi-tal and metharbital. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 421–37

    Google Scholar 

  52. Hooper WD, Qing MS. The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mepho-barbital in humans. Clin Pharmacol Ther 1990; 48(6): 633–40

    Article  PubMed  CAS  Google Scholar 

  53. van Heiningen PNM, Eve MD, Oosterhuis B, et al. The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine. Clin Pharmacol Ther 1991; 50(4): 410–9

    Article  PubMed  Google Scholar 

  54. Ochs HR, Otten H, Greenblatt DJ, et al. Diazepam absorption: effects of age, sex and billroth gastrectomy. Dig Dis Sci 1982; 27(3): 225–30

    Article  PubMed  CAS  Google Scholar 

  55. Divoll M, Greenblatt DJ, Ochs HR, et al. Absolute bioavaila-bility of oral and intramuscular diazepam: effects of age and sex. Anesth Analg 1983; 62: 1–8

    Article  PubMed  CAS  Google Scholar 

  56. Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther 1980; 27(3): 301–12

    Article  PubMed  CAS  Google Scholar 

  57. Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975; 55: 347–59

    Article  PubMed  CAS  Google Scholar 

  58. Ochs HR, Greenblatt DJ, Divoll M, et al. Diazepam kinetics in relation to age and sex. Pharmacology 1981; 23: 24–30

    Article  PubMed  CAS  Google Scholar 

  59. Macklon AF, Barton M, James O, et al. The effect of age on the pharmacokinetics of diazepam. Clin Sci 1980; 59: 479–83

    PubMed  CAS  Google Scholar 

  60. Greenblatt DJ, Divoll M, Surendra KP, et al. Clobazam kinetics in the elderly. Br J Clin Pharmacol 1981; 12: 631–6

    Article  PubMed  CAS  Google Scholar 

  61. Greenblatt DJ, Divoll M, Surendra KP, et al. Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation. Clin Pharmacokinet 1983; 8: 83–94

    Article  PubMed  CAS  Google Scholar 

  62. Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther 1988; 44(5): 558–65

    Article  PubMed  CAS  Google Scholar 

  63. Grant SM, Heel RC. Vigabatrin: a review of its pharmacody-namic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41(6): 889–926

    Article  PubMed  CAS  Google Scholar 

  64. Rey E, Pons G, Olive G. Vigabatrin clinical pharmacokinetics. Clin Pharmacokinet 1992; 23(4): 267–78

    Article  PubMed  CAS  Google Scholar 

  65. Ben-Menachem E. Vigabatrin. Epilepsia 1995; 36 Suppl. 2: S95–104

    Article  PubMed  CAS  Google Scholar 

  66. Goa KL, Ross SR, Chrisp P. Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46(1): 152–76

    Article  PubMed  CAS  Google Scholar 

  67. Posner J, Holdich T, Chrome P. Comparison of lamotrigine pharmacokinetics in young and elderly healthy volunteers. J Pharm Med 1991; 1: 121–8

    Google Scholar 

  68. Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46(3): 4099–27

    Google Scholar 

  69. Boyd RA, Bockbrader HN, Turck D, et al. Effect of subject age on the single dose pharmacokinetics of orally administered gabapentin (CI-945) [abstract]. Pharm Res 1990; 7: S215

    Google Scholar 

  70. Comstock TI, Sica DA, Bockbrader HN, et al. Gabapentin pharmacokinetics in subjects with various degrees of renal function [abstract]. J Clin Pharmacol 1990; 30: 862

    Google Scholar 

  71. Turner N, Scarpace PJ, Lowenthal DT. Geriatric pharmacology: basic and clinical considerations. Ann Rev Pharmacol Toxicol 1992; 32: 271–302

    Article  Google Scholar 

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Authors and Affiliations

  1. Conjoint Endocrine Laboratory, Royal Brisbane Hospital, Brisbane, Queensland, 4029, Australia

    Iren Bernus

  2. Department of Medicine, University of Queensland at Royal Brisbane Hospital, Brisbane, Queensland, Australia

    Ronald G. Dickinson, Wayne D. Hooper & Mervyn J. Eadie

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  1. Iren Bernus
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  2. Ronald G. Dickinson
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Bernus, I., Dickinson, R.G., Hooper, W.D. et al. Anticonvulsant Therapy in Aged Patients. Drugs & Aging 10, 278–289 (1997). https://doi.org/10.2165/00002512-199710040-00004

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