Abstract
There is a continuously growing population of older surgical patients who require an increasing number of anaesthetics and sedation. Pharmacokinetic and pharmacodynamic changes associated with increasing age are often not appreciated enough. Dose requirements for midazolam, a benzodiazepine commonly used for outpatient procedures, have been demonstrated in prospective studies to decrease with increasing age. On the other hand, rigorous prospective studies investigating the effect of age on the induction doses of other intravenous anaesthetics, such as thiopental sodium or propofol, are missing.
In addition, many of those patients take multiple drugs for medical problems often not related to the procedure. Drug interactions with anaesthetics are likely to occur, but are not well documented.
In this review we have summarised the documented and clinically relevant drug interactions with anaesthetics in the elderly population. We have identified a significant lack of scientific and outcome data and the need for more studies and education.
Similar content being viewed by others
References
Klopfenstein CE, Herrmann FR, Michel JP, et al. The influence of an aging surgical population on the anesthesia workload: a ten-year survey. Anesth Analg 1998; 86(6): 1165–70
Angus DC, Kelley MA, Schmitz RJ, et al. Caring for the critically ill patient: current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA 2000 Dec 6; 284(21): 2762–70
Turnheim K. Drug dosage in the elderly: is it rational? Drugs Aging 1998; 13(5): 357–79
Dodds C. Anaesthetic drugs in the elderly. Pharmacol Ther 1995; 66(2): 369–86
Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998 Jul; 35(1): 49–64
Turner N, Scarpace PJ, Lowenthal DT. Geriatric pharmacology: basic and clinical considerations. Annu Rev Pharmacol Toxicol 1992; 32: 271–302
Catterson ML, Preskorn SH, Martin RL. Pharmacodynamic and pharmacokinetic considerations in geriatric psychopharmacology. Psychiatr Clin North Am 1997; 20(1): 205–18
Feely J, Coakley D. Altered pharmacodynamics in the elderly. Clin Geriatr Med 1990 May; 6(2): 269–83
Fujita S. Aging and drug metabolism: alteration of liver drug metabolizing ability in male rats. Is it functional deterioration or feminization of the liver? Yakugaku Zasshi 1991 Nov; 111(11): 627–46
Jones AG, Hunter JM. Anaesthesia in the elderly: special considerations. Drugs Aging 1996; 9(5): 319–31
Klotz U. Effect of age on pharmacokinetics and pharmacodynamics in man. Int J Clin Pharmacol Ther 1998 Nov; 36(11): 581–5
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
Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age: a simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987 Jan; 240(1): 159–66
Lemmens HJ, Bovill JG, Hennis PJ, et al. Age has no effect on the pharmacodynamics of alfentanil. Anesth Analg 1988 Oct; 67(10): 956–60
Avram MJ, Krejcie TC, Niemann CU, et al. Isoflurane alters the recirculatory pharmacokinetics of physiologic markers. Anesthesiology 2000 Jun; 92(6): 1757–68
Gepts E. Pharmacokinetic concepts for TCI anaesthesia. Anaesthesia 1998 Apr; 53Suppl. 1: 4–12
Henthorn TK, Krejcie TC, Niemann CU, et al. Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective. Anesthesiology 1999 Dec; 91(6): 1733–43
Hull CJ. How far can we go with compartmental models? Anesthesiology 1990 Mar; 72(3): 399–402
Krejcie TC, Avram MJ. What determines anesthetic induction dose? It’s the front-end kinetics, doctor! Anesth Analg 1999 Sep; 89(3): 541–4
Bailey JM. Technique for quantifying the duration of intravenous anesthetic effect. Anesthesiology 1995 Nov; 83(5): 1095–103
Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992 Mar; 76(3): 334–41
Schraag S, Mohl U, Hirsch M, et al. Recovery from opioid anesthesia: the clinical implication of context-sensitive half-times. Anesth Analg 1998 Jan; 86(1): 184–90
Davidson MH. Does differing metabolism by cytochrome p450 have clinical importance? Curr Atheroscler Rep 2000; 2(1): 14–9
Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000 Jan; 38(1): 41–57
Dresser GK, Bailey DG. A basic conceptual and practical overview of interactions with highly prescribed drugs. Can J Clin Pharmacol 2002 Winter; 9(4): 191–8
Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998; 38: 389–430
Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3(1): 13–37
Miners JO. Evolution of drug metabolism: hitchhiking the technology bandwagon. Clin Exp Pharmacol Physiol 2001; 29(11): 1040–4
Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 2002; 34: 83–448
Tanaka E. Clinically important pharmacokinetic drug-drug interactions of cytochrome P450 enzymes. J Clin Pharm Ther 1998; 23(6): 403–16
Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with CoA reductase inhibitors. Clin Pharmacokinet 2002; 41(5): 343–70
Paspatis GA, Manolaraki M, Xirouchakis G, et al. Synergistic sedation with midazolam and propofol versus midazolam and pethidine in colonoscopies: a prospective, randomized study. Am J Gastroenterol 2002 Aug; 97(8): 1963–7
Reimann FM, Samson U, Derad I, et al. Synergistic sedation with low-dose midazolam and propofol for colonoscopies. Endoscopy 2000 Mar; 32(3): 239–44
Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology 2003 Feb; 98(2): 312–22
Reves JG, Glass PSA, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In: Miller RD, editor. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000: 228–72
van Hemelrijck J, White PF. Nonopioid intravenous anesthesia. In: Barash PG, Cullen BF, Stoelting RK, editors. Clinical anesthesia. 3rd ed. Philadelphia: Lippincott-Raven Publishers, 1996: 311–27
Fragen RJ. Infusions of intravenous anesthetics. In: Fragen RJ, editor. Drug infusions in anesthesiology. 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1996
McCollum JS, Dundee JW. Comparison of induction characteristics of four intravenous anaesthetic agents. Anaesthesia 1986 Oct; 41(10): 995–1000
Hudson RJ, Stanski DR, Burch PG. Pharmacokinetics of methohexital and thiopental in surgical patients. Anesthesiology 1983 Sep; 59(3): 215–9
Avram MJ, Sanghvi R, Henthorn TK, et al. Determinants of thiopental induction dose requirements. Anesth Analg 1993 Jan; 76(1): 10–7
Bischoff KB, Dedrick RL. Thiopental pharmacokinetics. J Pharm Sci 1968 Aug; 57(8): 1346–51
White PF. Clinical pharmacology of intravenous induction drugs. Int Anesthesiol Clin 1988 Summer; 26(2): 98–104
Olsen RW. Barbiturates. Int Anesthesiol Clin 1988 Winter; 26(4): 254–61
Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol Scand 1987 May; 31(4): 352–4
Stibolt O, Wachowiak-Andersen G. Altered response to intravenous thiopental and succinylcholine in acute amphetamine abuse. Acta Anaesthesiol Scand 2002 May; 46(5): 609–10
Kaukinen S, Eerola M, Ylitalo P. Prolongation of thiopentone anaesthesia by probenecid. Br J Anaesth 1980 Jun; 52(6): 603–7
Wilder-Smith OH, Ravussin PA, Decosterd LA, et al. Midazolam premedication and thiopental induction of anaesthesia: interactions at multiple end-points. Br J Anaesth 1999 Oct; 83(4): 590–5
Lim TA, Inbasegaran K. Midazolam premedication and thiopental induction of anaesthesia. Br J Anaesth 2000 Jul; 85(1): 175–6
Homer TD, Stanski DR. The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology 1985 Jun; 62(6): 714–24
Stanski DR, Maitre PO. Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology 1990 Mar; 72(3): 412–22
Davis AW, Heavner JE. Polypharmacy, age, and scheduled surgery. J Clin Anesth 2002 Aug; 14(5): 329–34
Sear JW, Higham H. Issues in the perioperative management of the elderly patient with cardiovascular disease. Drugs Aging 2002; 19(6): 429–51
Cillo JE, Jr. Propofol anesthesia for outpatient oral and maxillofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87(5): 530–8
Vargo JJ, Zuccaro Jr G, Dumot JA, et al. Gastroenterologistadministered propofol versus meperidine and midazolam for advanced upper endoscopy: a prospective, randomized trial. Gastroenterology 2002 Jul; 123(1): 8–16
Wehrmann T, Kokabpick S, Lembcke B, et al. Efficacy and safety of intravenous propofol sedation during routine ERCP: a prospective, controlled study. Gastrointest Endosc 1999 Jun; 49(6): 677–83
Miller LJ, Wiles-Pfeifler R. Propofol for the long-term sedation of a critically ill patient. Am J Crit Care 1998 Jan; 7(1): 73–6
Marinella MA. Propofol for sedation in the intensive care unit: essentials for the clinician. Respir Med 1997 Oct; 91(9): 505–10
Deegan RJ. Propofol: a review of the pharmacology and applications of an intravenous anesthetic agent. Am J Med Sci 1992 Jul; 304(1): 45–9
Dundee JW, Clarke RS. Propofol. Eur J Anaesthesiol 1989 Jan; 6(1): 5–22
Kanto JH. Propofol, the newest induction agent of anesthesia. Int J Clin Pharmacol Ther Toxicol 1988 Jan; 26(1): 41–57
Skues MA, Prys-Roberts C. The pharmacology of propofol. J Clin Anesth 1989; 1(5): 387–400
Trapani G, Altomare C, Liso G, et al. Propofol in anesthesia: mechanism of action, structure-activity relationships, and drug delivery. Curr Med Chem 2000 Feb; 7(2): 249–71
Shafer SL. Advances in propofol pharmacokinetics and pharmacodynamics. J Clin Anesth 1993 Nov–Dec; 5 (6 Suppl. 1): 14S–21S
Langley MS, Heel RC. Propofol: a review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic. Drugs 1988 Apr; 35(4): 334–72
Kirkpatrick T, Cockshott ID, Douglas EJ, et al. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth 1988 Feb; 60(2): 146–50
Shafer A, Doze VA, Shafer SL, et al. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988 Sep; 69(3): 348–56
Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999 Jun; 90(6): 1502–16
Carrasco G, Cabre L, Sobrepere G, et al. Synergistic sedation with propofol and midazolam in intensive care patients after coronary artery bypass grafting. Crit Care Med 1998 May; 26(5): 844–51
Cressey DM, Claydon P, Bhaskaran NC, et al. Effect of midazolam pretreatment on induction dose requirements of propofol in combination with fentanyl in younger and older adults. Anaesthesia 2001 Feb; 56(2): 108–13
Keita H, Peytavin G, Giraud O, et al. Aging prolongs recovery of psychomotor functions at emergence from propofol-alfentanil anaesthesia. Can J Anaesth 1998 Dec; 45(12): 1211–4
Ropcke H, Konen-Bergmann M, Cuhls M, et al. Propofol and remifentanil pharmacodynamic interaction during orthopedic surgical procedures as measured by effects on bispectral index. J Clin Anesth 2001 May; 13(3): 198–207
Seifert H, Schmitt TH, Gultekin T, et al. Sedation with propofol plus midazolam versus propofol alone for interventional endoscopic procedures: a prospective, randomized study. Aliment Pharmacol Ther 2000 Sep; 14(9): 1207–14
Taylor E, Ghouri AF, White PF. Midazolam in combination with propofol for sedation during local anesthesia. J Clin Anesth 1992 May–Jun; 4(3): 213–6
Walder B, Borgeat A, Suter PM, et al. Propofol and midazolam versus propofol alone for sedation following coronary artery bypass grafting: a randomized, placebo-controlled trial. Anaesth Intensive Care 2002 Apr; 30(2): 171–8
Giese JL, Stanley TH. Etomidate: a new intravenous anesthetic induction agent. Pharmacotherapy 1983 Sep–Oct; 3(5): 251–8
Preziosi P, Vacca M. Adrenocortical suppression and other endocrine effects of etomidate. Life Sci 1988; 42(5): 477–89
Arden JR, Holley FO, Stanski DR. Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response. Anesthesiology 1986 Jul; 65(1): 19–27
Irifune M, Shimizu T, Nomoto M, et al. Ketamine-induced anesthesia involves the N-methyl-D-aspartate receptor-channel complex in mice. Brain Res 1992 Nov 20; 596(1–2): 1–9
Klepstad P, Maurset A, Moberg ER, et al. Evidence of a role for NMDA receptors in pain perception. Eur J Pharmacol 1990 Oct 23; 187(3): 513–8
Oye I. Ketamine analgesia, NMDA receptors and the gates of perception. Acta Anaesthesiol Scand 1998 Aug; 42(7): 747–9
Chang T, Glazko AJ. Biotransformation and disposition of ketamine. Int Anesthesiol Clin 1974 Summer; 12(2): 157–77
White PF, Johnston RR, Pudwill CR. Interaction of ketamine and halothane in rats. Anesthesiology 1975 Feb; 42(2): 179–86
Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981 Jan; 53(1): 27–30
Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981 Aug; 53(8): 805–10
White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982 Feb; 56(2): 119–36
Soliman MG, Brindle GF, Kuster G. Response to hypercapnia under ketamine anaesthesia. Can Anaesth Soc J 1975 Jul; 22(4): 486–94
Dundee JW, Bovill JG, Clarke RS, et al. Problems with ketamine in adults [abstract]. Anaesthesia 1971 Jan; 26(1): 86
Garfield JM, Garfield FB, Stone JG, et al. A comparison of psychologic responses to ketamine and thiopental: nitrous oxide: halothane anesthesia. Anesthesiology 1972 Apr; 36(4): 329–38
Kawaguchi M, Sakamoto T, Inoue S, et al. Low dose propofol as a supplement to ketamine-based anesthesia during intraoperative monitoring of motor-evoked potentials. Spine 2000 Apr 15; 25(8): 974–9
Bell RF. Low-dose subcutaneous ketamine infusion and morphine tolerance. Pain 1999; 83(1): 101–3
Eilers H, Philip LA, Bickler PE, et al. The reversal of fentanyl-induced tolerance by administration of “small-dose” ketamine. Anesth Analg 2001 Jul; 93(1): 213–4
Greenblatt DJ. Pharmacology of benzodiazepine hypnotics. J Clin Psychiatry 1992 Jun; 53 Suppl.: 7–13
Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 2002 Jun; 22(3): 285–93
Bell GD, Spickett GP, Reeve PA, et al. Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin Pharmacol 1987; 23(2): 241–3
Gray SL, Lai KV, Larson EB. Drug-induced cognition disorders in the elderly: incidence, prevention and management. Drug Saf 1999; 21(2): 101–22
Closser MH. Benzodiazepines and the elderly: a review of potential problems. J Subst Abuse Treat 1991; 8(1–2): 35–41
Greenblatt DJ. Benzodiazepine hypnotics: sorting the pharmacokinetic facts. J Clin Psychiatry 1991 Sep; 52 Suppl.: 4–10
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (Part I). Clin Pharmacokinet 1991 Sep; 21(3): 165–77
Lechin F, van der Dijs B, Benaim M. Benzodiazepines: tolerability in elderly patients. Psychother Psychosom 1996; 65(4): 171–82
Reves JG, Fragen RJ, Vinik HR, et al. Midazolam: pharmacology and uses. Anesthesiology 1985 Mar; 62(3): 310–24
Shorr RI, Robin DW. Rational use of benzodiazepines in the elderly. Drugs Aging 1994 Jan; 4(1): 9–20
Amrein R, Hetzel W. Pharmacology of Dormicum (midazolam) and Anexate (flumazenil). Acta Anaesthesiol Scand Suppl 1990; 92: 6–15
Mohler H, Richards JG. The benzodiazepine receptor: a pharmacological control element of brain function. Eur J Anaesthesiol Suppl 1988; 2: 15–24
Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. Eur J Anaesthesiol Suppl 2002 Jan; 300(1): 2–8
Forster A, Gardaz JP, Suter PM, et al. Respiratory depression by midazolam and diazepam. Anesthesiology 1980 Dec; 53(6): 494–7
Alexander CM, Gross JB. Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesth Analg 1988 Apr; 67(4): 377–82
Alexander CM, Teller LE, Gross JB. Slow injection does not prevent midazolam-induced ventilatory depression. Anesth Analg 1992 Feb; 74(2): 260–4
Bailey PL, Pace NL, Ashburn MA, et al. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990 Nov; 73(5): 826–30
Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993 Mar; 53(3): 298–305
Palkama VJ, Isohanni MH, Neuvonen PJ, et al. The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil. Anesth Analg 1998; 87(1): 190–4
Palkama VJ, Ahonen J, Neuvonen PJ, et al. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999 Jul; 66(1): 33–9
Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Eilers, H., Niemann, C.U. Clinically Important Drug Interactions with Intravenous Anaesthetics in Older Patients. Drugs Aging 20, 969–980 (2003). https://doi.org/10.2165/00002512-200320130-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200320130-00002