Pharmacodynamics in Older Adults: A Review

McLean, 2004, Aging biology and geriatric clinical pharmacology, Pharmacol Rev, 56, 163, 10.1124/pr.56.2.4 Klotz, 1998, Effect of age on pharmacokinetics and pharmacodynamics in man, IntJ Clin Pharmacol Ther, 36, 581 Turnheim, 2003, When drug therapy gets old: Pharmacokinetics and pharmacodynamics in the elderly, Exp Gerontol, 38, 843, 10.1016/S0531-5565(03)00133-5 Hammerlein, 1998, Pharmacokinetic and pharmacodynamic changes in the elderly.Clinical implications, Clin Pharmacokinet, 35, 49, 10.2165/00003088-199835010-00004 Jackson, 1994, Pharmacodynamics in the elderly, J R Soc Med, 87, 5 Burton, 2005, Bridging the gap: Ageing, pharmacokinetics and pharmacodynamics, J Pharm Pharmacol, 57, 671, 10.1211/0022357056163 Sharer, 2000, The pharmacology of anesthetic drugs in el- derly patients, Anesthesiol Clin North Am, 18, 1, 10.1016/S0889-8537(05)70146-2 Vuyk, 2003, Pharmacodynamics in the elderly, Best Pract Res Clin Anaesthesiol, 17, 207, 10.1016/S1521-6896(03)00008-9 Mangoni, 2003, Age-related changes in pharmacokinetics and pharmacodynamics: Basic principles and practical applications, BrJ Clin Pharmacol, 57, 6, 10.1046/j.1365-2125.2003.02007.x Noble, 2003, Drug therapy in the elderly, Metabolism, 52, 27, 10.1016/S0026-0495(03)00298-1 Williams, 2003, Cardiovascular drug therapy in the elderly: Theoretical and practical considerations, Drugs Aging, 20, 445, 10.2165/00002512-200320060-00004 Papp, 1991, Cardiac responses to drugs at the extremes of age, Therapie, 46, 283 Abernethy, 1990, Altered pharmacodynamics of cardiovascular drugs and their relation to altered pharmacokinetics in elderly patients, Clin Geriatr Med, 6, 285, 10.1016/S0749-0690(18)30617-7 Collins, 1990, Age-related changes in autonomic control: The use of beta blockers in the treatment of hypertension, Cardiovasc Drugs Ther, 4, 1257, 10.1007/BF00114230 Lichtman, 2003, Pharmacology of antineoplastic agents in older cancer patients, Crit Rev Oncol Hematol, 46, 101, 10.1016/S1040-8428(02)00120-8 Rodriguez-Julbe, 2004, Antibiotics in older adults, P R Health SciJ, 23, 25 Peters, 2006, Ageing and the brain, Postgrad Meal J, 82, 84, 10.1136/pgmj.2005.036665 Toornvliet, 2006, Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(ll)C]verapamil and positron emission tomography, Clin Pharmacol Ther, 79, 540, 10.1016/j.clpt.2006.02.004 Tupler, 1995, Alcohol pharmacodynamics in young-clderly adults contrasted with young and middle-aged subjects, Psychopharmacology (Berl), 118, 460, 10.1007/BF02245947 Fleishaker, 1992, Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intrave- nous dosing in healthy young and elderly volunteers, J Clin Psychopharmacol, 12, 403, 10.1097/00004714-199212000-00006 Kroboth, 1990, Alprazolam in the elderly: Pharmacokinetics and pharmacodynamics during multiple dosing, Psychopharmacology (Berl), 100, 477, 10.1007/BF02243999 Smith, 1987, Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects, Psychopharmacology (Berl), 93, 105, 10.1007/BF02439595 Kaplan, 1998, Singledose pharmacokinetics and pharmacodynamics of alprazolam in elderly and young subjects, J Clin Pharmacol, 38, 14, 10.1002/j.1552-4604.1998.tb04370.x Swift, 1985, Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly, Br J Clin Pharmacol, 20, 119, 10.1111/j.1365-2125.1985.tb05041.x Albrecht, 1999, The effect of age on the pharmacokinetics and pharmacodynamics of midazolam, Clin Pharmacol Ther, 65, 630, 10.1016/S0009-9236(99)90084-X Jacobs, 1995, Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam, Anesth Analg, 80, 143 Platten, 1998, Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction, Clin Pharmacol Ther, 63, 552, 10.1016/S0009-9236(98)90106-0 Sonne, 1991, Single dose pharmacokinetics and pharmacodynamics of oral oxazepam in very elderly institntionalised subjects, Br J Clin Pharmacol, 31, 719, 10.1111/j.1365-2125.1991.tb05602.x Greenblatt, 2004, Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A sub- strate, Clin Pharmacol Ther, 76, 467, 10.1016/j.clpt.2004.07.009 Greenblatt, 1991, Sensitivity to triazolam in the elderly, NEnglJMed, 324, 1691, 10.1056/NEJM199106133242403 Robin, 1996, Increased baseline sway contributes to increased losses of balance in older people following triazolam, JAm Geriatr Soc, 44, 300, 10.1111/j.1532-5415.1996.tb00919.x Ray, 1989, Benzodiazepines of long and short elimination half-life and the risk of hip fracture, JAMA, 262, 3303, 10.1001/jama.1989.03430230088031 Ray, 2000, Benzodiazepines and the risk of falls in nursing home residents, JAm Geriatr Soc, 48, 682 685 Cumming, 2003, Benzodiazepines and risk of hip fractures in older people: A review of the evidence, CNS Drugs, 17, 825, 10.2165/00023210-200317110-00004 Greenblatt, 1984, Effect of age, gender, and obesity on midazolam kinetics, Anesthesiology, 61, 27, 10.1097/00000542-198461010-00006 Servin, 1987, Pharmacokinetics ofmidazolam used as an intravenous induction agent lfbr patients over 80 years of age, Eur J Anaesthesiol, 4, 1 Kanto, 1981, Effect of age on the pharmacokinetics and sedative effects of flunitrazepam, Int J Clin Pharmacol Ther Toxicol, 19, 400 Pomara, 1998, The acute and chronic perl~brmance effects of alprazolam and loraze pam in the elderly: Relationship to duration of treatment and self-rated sedation, Psyehopharmacol Bull, 34, 139 Ruano, 1996, Age-related modifications on the GABAA receptor binding properties from Wistar rat prefrontal cortex, Brain Res, 738, 103, 10.1016/0006-8993(96)00764-0 Bickfbrd, 2000, Benzodiazepine modulation of GABAergic responses is intact in the cerebellum of aged F344 rats, Neurosci Lett, 291, 187, 10.1016/S0304-3940(00)01417-8 Sundman, 1997, GABA uptake sites in frontal cortex from suicide victims and in aging, Neuropsyehobiology, 35, 11, 10.1159/000119324 Arden, 1986, Increased sensitivity to etomidate in the elderly: Initial distribution versus altered brain response, Anesthesiology, 65, 19, 10.1097/00000542-198607000-00004 Schnider, 1999, The influence of age on propofbl pharmacodynamics, Anesthesiology, 90, 1502, 10.1097/00000542-199906000-00003 Kazama, 2000, Optimal propofbl plasma concentration during upper gastrointestinal endoscopy in young, middle-aged, and elderly patients, Anesthesiology, 93, 662, 10.1097/00000542-200009000-00014 Stanski, 1990, Population pharmacokinetics and pharmacodynamics of thiopental: The effect of age revisited, Anesthesiology, 72, 412, 10.1097/00000542-199003000-00003 Kitts, 1990, Pharmacokinetics and pharmacodynamics of atracurium in the elderly, Anesthesiology, 72, 272, 10.1097/00000542-199002000-00011 Sorooshian, 1996, Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly adult patients, Anesthesiology, 84, 1083, 10.1097/00000542-199605000-00010 Gariepy, 1993, Influence of aging on the pharmacokinetics and pharmacodynamics ofdox acurium, Clin Pharmacol Ther, 53, 340, 10.1038/clpt.1993.30 Matteo, 1985, Pharmacokinetics and pharmacodynamics of d-tubocurarine and metocurine in the elderly, Anesth Analg, 64, 23, 10.1213/00000539-198501000-00005 Duvaldestin, 1982, Pharmacokinetics, pharmacodynamics, and dose-response relationships of pancuronium in control and elderly subjects, Anesthesiology, 56, 36, 10.1097/00000542-198201000-00008 Rupp, 1987, Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults, Anesthesiology, 67, 45, 10.1097/00000542-198707000-00008 Ornstein, 1992, Pharmacokinetics and pharmacodynamics of pipecuronium bromide (Arduan) in elderly surgical patients, Anesth Analg, 74, 841, 10.1213/00000539-199206000-00011 Matteo, 1993, Pharmacokinetics and pharmacodynamics of rocuronium (Org 9426) in elderly surgical patients, Anesth Analg, 77, 1193, 10.1213/00000539-199312000-00019 Matteo, 1990, Pharmacokinetics and pharmacodynamics ofedrophonium in elderly surgical patients, Anesth Analg, 71, 334, 10.1213/00000539-199010000-00003 Scott, 1987, Decreased fentanyl and alfenanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation, JPharmacol Exp Ther, 240, 159 Minto, 1997, Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil, I. Model development. Anesthesiology, 86, 10 Z MacDonald, 1993, A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril, Br J Clin Pharmacol, 36, 201, 10.1111/j.1365-2125.1993.tb04217.x MacDonald, 1993, The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril, BrJ Clin Pharmacol, 36, 205, 10.1111/j.1365-2125.1993.tb04218.x Lees, 1987, Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment, Clin Pharmacol Ther, 41, 597, 10.1038/clpt.1987.81 Arner, 1994, Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension, J Cardiovasc Pharmacol, 23, S44, 10.1097/00005344-199406001-00010 Williams, 1989, A pharmacokinetic study of cilazapril in elderly and young volunteers, BrJ Clin Pharmacol, 27, 211S, 10.1111/j.1365-2125.1989.tb03484.x Lees, 1988, Influence of age on the pharmacokinetics and pharmacodynamics ofperindopril, Clin Pharmacol Ther, 44, 418, 10.1038/clpt.1988.174 Rakhit, 1987, Pharmacokinetics of pentopril in the elderly, Br J Clin Pharmacol, 24, 351, 10.1111/j.1365-2125.1987.tb03180.x Abernethy, 1994, An overview of the pharmacokinetics and pharmacodynamics of amlodipine in elderly persons with systemic hypertension, Am J Cardiol, 73, 10A, 10.1016/0002-9149(94)90269-0 Abernethy, 1990, Effects of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: Pharmacodynamics in relation to disposition, Clin Pharmacol Ther, 48, 76, 10.1038/clpt.1990.120 Robertson, 1988, Age-related changes in pharmacokinetics and pharmacodynamics of nifedipine, Br J Clin Pharmacol, 25, 297, 10.1111/j.1365-2125.1988.tb03307.x Donnelly, 1990, Factors influencing the responses to calcium antagonists in elderly patients with hypertension and ischaemic heart disease, Exp Gerontol, 25, 375, 10.1016/0531-5565(90)90075-D Abernethy, 1993, Stereoselective verapamil disposition and dynamics in aging during racemic verapamil administration, J Pharmt~col Exp Ther, 266, 904 Abernethy, 1986, Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Altered electrocardiographic and hypotensive responses, Ann Intern Med, 105, 329, 10.7326/0003-4819-105-3-329 Carosella, 1989, Verapamil disposition and cardiovascular effects in elderly patients after single intravenous and oral doses, Cardiovasc Drugs Ther, 3, 417, 10.1007/BF01858113 Schwartz, 1993, Aging effects on stercoselective pharmacokinetics and pharmacodynamics of verapamil, J Pharmacol Exp Ther, 265, 690 Gupta, 1995, Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norvera- pamil, Br J Clin Pharmacol, 40, 325, 10.1111/j.1365-2125.1995.tb04554.x Montamat, 1989, Calcium antagonists in geriatric patients: Diltiazem in elderly persons with hypertension, Clin Pharmacol Ther, 45, 682, 10.1038/clpt.1989.90 Ellenbogen, 1985, Frequency-dependent effects of verapamil on atrioventricular nodal conduction in man, Circulation, 72, 344, 10.1161/01.CIR.72.2.344 Vestal, 1979, Reduced beta-adrenoceptor sensitivity in the elderly, Clin Pharmacol Ther, 26, 181, 10.1002/cpt1979262181 Turner, 1999, Effects of age and gender on the cardiovascular responses to isoproterenol, J Gerontol A Biol Sci Med Sci, 54, B393, 10.1093/gerona/54.9.B393 Scott, 1995, The effects of age on the pharmacokinetics and pharmacodynamics of cardiovascular drugs: Application of concentration-effect modeling, 2. Acebutolol. AmJ Ther, 2, 537, 10.1097/00045391-199508000-00004 Abernethy, 1987, Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension, Am J Cardiol, 60, 697, 10.1016/0002-9149(87)90385-7 MacPhee, 1991, The effects of age on the pharmacokinetics, antihypertensive efficacy and general tolerability of dilevalol, Br J Clin Pharmacol, 32, 591, 10.1111/j.1365-2125.1991.tb03957.x Meredith, 1995, Effects of age on the pharmacokinetics and pharmacodynamics of cardiovascular drugs: Application of concentration-effect modeling, 3. Trimazosin. AmJ Ther, 2, 541, 10.1097/00045391-199508000-00005 Andros, 1996, The effect of aging on the pharmacokinetics and pharmacodynamics ofprazosin, EurJ Clin Pharmacol, 50, 41, 10.1007/s002280050067 Stratton, 2003, Effects of aging on cardiovascular responses to parasympathetic withdrawal, JAm Coll Cardiol, 41, 2077, 10.1016/S0735-1097(03)00418-2 Lamy, 1991, Physiological changes due to age. Pharmacodynamic changes of drug action and implications for therapy, Drugs Aging, 1, 385, 10.2165/00002512-199101050-00006 Feldman, 1984, Alterations in leukocyte beta-receptor affinity with aging. A potential explanation for altered beta-adrenergic sensitivity in the elderly, N EnglJMed, 310, 815, 10.1056/NEJM198403293101303 Connolly, 1994, Peripheral mononuclear leucocyte beta adrenoceptors and non-specific bronchial responsiveness to methacholine in young and elderly normal subjects and asthmatic patients, Thorax, 49, 26, 10.1136/thx.49.1.26 Schocken, 1977, Reduced beta-adrenergic receptor concentrations in ageing man, Nature, 267, 856, 10.1038/267856a0 Doyle, 1982, Human lymphocyte beta-adrenoceptor density in relation to age and hypertension, J Cardiovase Pharmacol, 4, 738, 10.1097/00005344-198209000-00007 Landmann, 1981, High affinity beta-2-adrenergic receptors in mononuclear leukocytes: Similar density in young and old normal subjects, Life Sci, 29, 1761, 10.1016/0024-3205(81)90186-7 Abrass, 1981, Human lymphocyte beta-adrenergic receptors are unaltered with age, J Gerontol, 36, 298, 10.1093/geronj/36.3.298 Xiao, 1998, Age-associated reductions in cardiac betal- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases, J Clin Invest, 101, 1273, 10.1172/JCI1335 White, 1994, Age-related changes in beta-adrenergic neuroeffector systems in the human heart, Circulation, 90, 1225, 10.1161/01.CIR.90.3.1225 Brodde, 1995, Age- dependent changes in beta-adrenoceptor G-protein(s)- adenylyl cyclase system in human right atrium, J Cardiovasc Pharmacol, 26, 20, 10.1097/00005344-199507000-00004 Grossman, 2002, Why beta-blockers are not cardioprotective in elderly patients with hypertension, Curr Cardiol Rep, 4, 468, 10.1007/s11886-002-0108-3 Constantine, 1983, Effects of trimazosin and prazosin on blood pressure and on pressor responses to phenylephrine in rats, Am HeartJ, 106, 1216, 10.1016/0002-8703(83)90178-3 Barnett, 1999, Effects of age and gender on autonomic control of blood pressure dynamics, Hypertension, 33, 1195, 10.1161/01.HYP.33.5.1195 Kenney, 1994, Effect of age on renal blood flow during exercise, Aging (Milano), 6, 293 Jones, 2003, Baroreflex buffering is reduced with age in healthy men, Circulation, 107, 1770, 10.1161/01.CIR.0000057811.86187.88 Kaye, 2005, Sympathetic neuronal regulation of the heart in aging and heart failure, Cardiovase Res, 66, 256, 10.1016/j.cardiores.2005.02.012 Brodde, 1982, Age- dependent decrease of alpha 2-adrenergic receptor number in human platelets, Eur J PharmacoL, 81, 345, 10.1016/0014-2999(82)90456-3 Li, 2003, Aging related changes in cardiac sympathetic function in humans, assessed by 6-18F-fluorodopamine PET scanning, J Nucl Med, 44, 1599 Turnheim, 1998, Drug dosage in the elderly, Is it rational? Drugs Aging, 13, 357, 10.2165/00002512-199813050-00003 Connolly, 1993, Ageing, late-onset asthma and the beta- adrenoceptor, Pharmaeol Ther, 60, 389, 10.1016/0163-7258(93)90029-D Madden, 2006, Normal aging impairs upregulation of the beta-adrenergic but not the alpha-adrenergic response: Aging and adrenergic upregulation, J Cardiovasc Pharmacol, 48, 153, 10.1097/01.fjc.0000246405.89380.48 Velez-Roa, 2003, Peripheral sympathetic control during dobutamine infusion: Effects of aging and heart failure, J Am Coil Cardiol, 42, 1605, 10.1016/j.jacc.2003.07.004 Mukai, 2003, Effect of systolic blood pressure and carotid stiffness on baroreflex gain in elderly subjects, J Gerontol A Biol Sci Med Sci, 58, 626, 10.1093/gerona/58.7.M626 Giessler, 1998, Age dependent decrease in the negative inotropic effect of carbachol on isolated human right atrium, Eur J Pharmacol, 357, 199, 10.1016/S0014-2999(98)00568-8 Brodde, 1998, Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies, J Clin Invest, 101, 471, 10.1172/JCI1113 Lakatta, 2002, The "heartbreak" of older age, Mol Interv, 2, 431, 10.1124/mi.2.7.431 Bao, 2005, Interactive effects of common beta2-adrenoceptor haplotypes and age on susceptibility to hypertension and receptor function, Hypertension, 46, 301, 10.1161/01.HYP.0000175842.19266.95 Muhlberg, 1986, Pharmacokinetics and pharmacodynamics of furosemide in geriatric patients, Arch Gerontol Geriatr, 5, 249, 10.1016/0167-4943(86)90026-9 Andreasen, 1984, The influence of age on renal and extrarenal effects of frusemide, Br J Clin Pharmacol, 18, 65, 10.1111/j.1365-2125.1984.tb05023.x Oberbauer, 1995, Pharmacokinetics and pharmacodynamics of the diuretic bumetanide in the elderly, Clin Pharmacol Ther, 57, 42, 10.1016/0009-9236(95)90264-3 Kerremans, 1983, Changes in pharmacokinetics and in effect of fnrosemide in the elderly, Clin Exp Hypertens A, 5, 271, 10.3109/10641968309048826 Kerremans, 1983, Furosemide kinetics and dynamics in aged patients, Clin Pharmacol Ther, 34, 181, 10.1038/clpt.1983.150 Muhlberg, 2001, The influence of age on the pharmacokinetics and pharmacody- namics of bemetizide and triamterene: A single and multiple dose study, Arch Gerontol Geriatr, 32, 265, 10.1016/S0167-4943(01)00089-9 Beermann, 1977, Elimination of furosemide in healthy subjects and in those with renal failure, Clin Pharmacol Ther, 22, 70, 10.1002/cpt197722170 Shepherd, 1977, Age as a determinant of sensitivity to warfarin, Br J Clin Pharmacol, 4, 315, 10.1111/j.1365-2125.1977.tb00719.x Swan, 2000, The pharmacokinetics and pharmacodynamics of argatroban: Effects of age, gender, and hepatic or renal dysfunction, Pharmacotherapy, 20, 318, 10.1592/phco.20.4.318.34881 Johansson, 2003, Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, Clin Pharmacokinet, 42, 381, 10.2165/00003088-200342040-00006 Russmann, 1997, Age-dependent differences in the anticoagulant effect ofphenprocoumon in patients after heart valve surgery, EurJ Clin Pharmacol, 52, 31, 10.1007/s002280050245 Fihn, 1996, for the National Consortium of Anticoagulation Clinics. The risk for and severity of bleeding complications in elderly patients treated with warfarin, Ann Intern Med, 124, 970, 10.7326/0003-4819-124-11-199606010-00004 Gurwitz, 1992, Aging and the anticoagulant response to warfarin therapy, Ann Intern Med, 116, 901, 10.7326/0003-4819-116-11-901 Wynne, 1996, Effect of age- ing upon warfarin dose requirements: A longitudinal study, Age Ageing, 25, 429, 10.1093/ageing/25.6.429 James, 1992, Factors affecting the maintenance dose of warfarin, J Clin Pathol, 45, 704, 10.1136/jcp.45.8.704 Mungall, 1985, Population pharmacokinetics of racemic warfarin in adult patients, J Pharmacokinet Biopharm, 13, 213, 10.1007/BF01065653 Hylek, 2001, Oral anticoagulants. Pharmacologic issues for use in the elderly, Clin Geriatr Med, 17, 1, 10.1016/S0749-0690(05)70102-6 Loebstein, 2001, Interindividual variability in sensitivity to warfarin--nature or nurture?, Clin Pharmacol Ther, 70, 159, 10.1067/mcp.2001.117444 Kamali, 2004, Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin, Clin Pharmacol Ther, 75, 204, 10.1016/j.clpt.2003.10.001 Marchionni, 1990, Age- related changes in the pharmacodynamics of intravenous glyceryl trinitrate, Aging (Milano), 2, 59 Meredith, 1995, The effects of age on the pharmacokinetics and pharmacodynamics of cardiovascular drugs: Application of concentration- effect modeling, Tolmesoxide. Am J Ther, 2, 532, 10.1097/00045391-199508000-00003 Miura, 2000, Effect of aging on the incidence of digoxin toxicity, Ann Pharmacother, 34, 427, 10.1345/aph.19103 Henry, 2003, Young and elderly type 2 diabetic patients inhaling insulin with the AERx Insulin Diabetes Management System: A pharmacoki- netic and pharmacodynamic comparison, JClin Pharmacol, 43, 1228, 10.1177/0091270003258657 Jaber, 1996, Pharmacokinetics and pharmacodynamics of glyburide in young and elderly patients with non-insulin-dependent diabetes mellitus, Ann Pharmacother, 30, 472, 10.1177/106002809603000507 Schwinghammer, 1991, Pharmacokinetics and pharmacodynamics of glyburide in young and elderly nondiabetic adults, Clin Pharm, 10, 532 Jaber, 1996, The influence of multiple dosing and age on the pharmacokinet- ics and pharmacodynamics of glipizide in patients with type II diabetes mellitus, Pharmacotherapy, 16, 760 Ferranini, 1996, for the European Group for the Study of Insulin Resistance (EGIR). Insulin action and age, Diabetes, 45, 947, 10.2337/diabetes.45.7.947 Fink, 1983, Mechanism of insulin resistance in aging, J Clin Invest, 71, 1523, 10.1172/JCI110908 Rowe, 1983, Characterization of the insulin resistance of aging, J Clin Invest, 71, 1581, 10.1172/JCI110914 De Nino, 2001, Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy non- obese women, Diabetes Care, 24, 925, 10.2337/diacare.24.5.925 Otsuki, 2005, Sex differences of age-dependent changes of insulin sensitivity in Japanese nondiabetic subjects, Diabetes Care, 28, 2590, 10.2337/diacare.28.10.2590a Utzschneider, 2004, Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function, Diabetes, 53, 2867, 10.2337/diabetes.53.11.2867 Meneilly, 1987, Insulin action in aging man: Evidence for issue-specific differences at low physiologic insulin levels, J Gerontol, 42, 196, 10.1093/geronj/42.2.196 Barbieri, 2001, Age- related insulin resistance: Is it an obligatory finding? The lesson from healthy centenarians, Diabetes Metab Res Rev, 17, 19, 10.1002/dmrr.178 Dipiro, 2002, Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill Medical Webber, 1992, Glucose tolerance in the elderly-- changes in insulin, C-peptide, and glucagon secretion, Wien Med Wochenschr, 142, 73 Browdows, 1992, Benefits and risks with glyburide and glipizide in elderly NIDDM patients, Diabetes Care, 15, 75, 10.2337/diacare.15.1.75 Shorr, 1996, Individual sulfonylureas and serious hypoglycemia in older people, JAm Geriatr Soc, 44, 751, 10.1111/j.1532-5415.1996.tb03729.x 2006, Glucophage [package insert] Sambol, 1995, Kidney function and age are both predictors of pharmacokinetics of metformin, J Clin Pharmacol, 35, 1094, 10.1002/j.1552-4604.1995.tb04033.x Tornatore, 1997, Cortisol pharmacodynamics after methylprednisolone administration in young and elderly males, J Clin Pharmacol, 37, 304, 10.1002/j.1552-4604.1997.tb04307.x Tornatore, 1998, CD4+ and CDS+ lymphocyte and cortisol response patterns in elderly and young males after methylprednisolone exposure, J Med, 29, 159 Katzung, 2004, Basic and Clinical Pharmacology., 9th ed New York, NY: Lange Medical Books/McGraw-Hill Thomas, 1984, The complications of systemic corticosteroid therapy in the elderly. A retrospective study, Gerontology, 30, 60, 10.1159/000212608 Fietta, 1994, Influence of aging on some specific and nonspecific mechanisms of the host defense system in 146 healthy subjects, Gerontology, 40, 237, 10.1159/000213591 Tornatore, 1994, Pharmacokinetics of methylprednisolone in elderly and young healthy males, JAm Geriatr Soc, 42, 1118, 10.1111/j.1532-5415.1994.tb06219.x Webster, 2004, Role of the hypothalamic- pituitary-adrenal axis, glucocorticoids and glucocorti- cold receptors in toxic sequelae of exposure to bacterial and viral products, J Endocrinol, 181, 207, 10.1677/joe.0.1810207 Abedin, 2005, Diversity of NKR expression in aging T cells and in T cells of the aged: The new frontier into the exploration of protective immunity in the elderly, Exp Gerontol, 40, 537, 10.1016/j.exger.2005.04.012