Experimental Gerontology 38 (2003) 843–853 www.elsevier.com/locate/expgero Review When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly Klaus Turnheima,b,* b a ¨ ¨ ¨ Institut fur Pharmakologie, Universitat Wien, Wahringer Str. 13a, Vienna A-1090, Austria ¨ Ludwig Boltzmann Institut fur Altersforschung, Donauspital im Sozialmedizinischem, Zentrum-Ost, Langobarden Str. 122, Wien A-1220, Austria Accepted 6 May 2003 Abstract The age-related changes in the functions and composition of the human body require adjustments of drug selection and dosage for old individuals. Drug excretion via the kidneys declines with age, the elderly should therefore be treated as renally insufficient patients. The metabolic clearance is primarily reduced with drugs that display high hepatic extraction (‘blood flow-limited metabolism’), whereas the metabolism of drugs with low hepatic extraction (‘capacity-limited metabolism’) usually is not diminished. Reduction of metabolic drug elimination is more pronounced in malnourished or frail subjects. The water content of the aging body decreases, the fat content rises, hence the distribution volume of hydrophilic compounds is reduced in the elderly, whereas that of lipophilic drugs is increased. Intestinal absorption of most drugs is not altered in the elderly. Aside of these pharmacokinetic changes, one of the characteristics of old age is a progressive decline in counterregulatory (homeostatic) mechanisms. Therefore drug effects are mitigated less, the reactions are usually stronger than in younger subjects, the rate and intensity of adverse effects are higher. Examples of drug effects augmented is this manner are postural hypotension with agents that lower blood pressure, dehydration, hypovolemia, and electrolyte disturbances in response to diuretics, bleeding complications with oral anticoagulants, hypoglycemia with antidiabetics, and gastrointestinal irritation with non-steroidal anti-inflammatory drugs. The brain is an especially sensitive drug target in old age. Psychotropic drugs but also anticonvulsants and centrally acting antihypertensives may impede intellectual functions and motor coordination. The antimuscarinic effects of some antidepressants and neuroleptic drugs may be responsible for agitation, confusion, and delirium in elderly. Hence drugs should be used very restrictively in geriatric patients. If drug therapy is absolutely necessary, the dosage should be titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose. q 2003 Elsevier Inc. All rights reserved. Keywords: Aging; Pharmacokinetics in the elderly; Pharmacodynamics in the elderly; Drug dosage; Gerontopharmacology; Drug metabolism; Renal drug excretion; Pharmacokinetic dosage guidelines; Antiaging drugs 1. Introduction Most of us want a long life, but that implies getting old. Aging is associated with many disconcerting problems, not the least of which concerns the efficacy and safety of drug therapy. The increase in life expectancy over the past decades makes this issue more acute, survival to old age seems to be more and more the norm. The beginning of senescence is insidious. Although this process commences after maturation, it manifests itself prominently and progressively in the post-reproductive * Tel.: þ43-1-4277x64110; fax: þ43-1-4277x9641. E-mail address:
[email protected] (K. Turnheim). 0531-5565/03/$ - see front matter q 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0531-5565(03)00133-5 stages of live. Society has agreed, rather arbitrarily, to define elderly as individuals aged 65 years and older. This review deals with the principles of drug use in the elderly and the age-related alterations in drug disposition and response, changes that result from the modifications of the functions and composition of the body associated with aging. The literature on the topic is vast, so this article makes no attempt to be comprehensive. 2. Biology of aging Survival to old age requires a protected habitat, as wild animals usually die early from extrinsic hazards such as infection, predation, starvation, or cold Li et al. The structure of many proteins is altered in old age. 1999).. which prevents telomere shortening. stochastic and developmental-genetic. respectively. Very old individuals tend to become frail. but this process may be responsible for atherosclerosis in later years. Aging entails a gradual decrease in physiological fitness and reduced ability to respond to environmental demands. for example. Troen. 3. 1998). 1995). 2000). In men and women there is agerelated hypogonadism. 2000). Support for the developmentalgenetic theories comes from the evidence that the maximal life span of animals is highly species-specific and that several genetic diseases in humans are known that display accelerated aging. Renal. free radicals or other environmental toxins occur randomly and accumulate with time. hepatic. and Down’s syndrome (Troen. Further. resulting in the decline in physiological fitness. Turnheim. Other age-related changes include reduction of the diffusing capacity of the lung. cardiac output decreases. on the other hand. resulting in a steady decline in arterial pO2 (Turnheim.844 K. and the lens protein. In the endocrine system. slows diastolic filling. 2003. Campisi. is associated with an increased risk of neoplasms (Chen et al. While reactivity against foreign antigens drops significantly in old age. Werner’s syndrome (adult progeria). The reduction in homeostatic capablities is a fundamental feature of senescence. elastin. Other age-related modifications of proteins are glycation and oxidation (Troen. and to a lesser degree cerebral blood flow declines. are decreased as are the concentrations of growth hormone and dehydroepiandrosterone (DHEA). The developmental-genetic theories. 2001. the repeated sequences found at the ends of chromosomes. and death. 1997). The susceptibility for infectious diseases and the emergence of tumors is increased in the elderly. possibly because of a decline in the function of the immune system.. for instance the Hutchinson-Gilford syndrome (classical early onset progeria in children). Protein-protein interactions may be responsible for the increased rigidity of practically all tissue in elderly. Because of these changes. have extended life spans. autoimmune reactions paradoxically increase (Wick and Grubeck-Loebenstein. The prevalence of hypothyroidism increases in the elderly (Canaris et al. Other age-related disorders that are explained along these lines are Alzheimer’s disease and prostate hypertrophy (Wick et al. 1991. 2002). 2002. For instance. with ‘mutation accumulation’ over time or selection of genes which serve the youthful organism but have deleterious effects later on. 2000. But hormone replacement therapy. These changes may contribute to defects of the muscular. At least some cells that express telomerase. for example there is increased crosslinking of extracellular matrix proteins such as collagen. The limited proliferative capacity of cells in culture. 1997. maturation. which is termed ‘replicative senescence’. skeletal. The effect of age on other organs will be discussed in the appropriate sections of this article. Butler et al. Tissue calcification. Pugh and Wei. propose that aging is genetically predetermined as part of the continuum of birth. Turnheim / Experimental Gerontology 38 (2003) 843–853 (Kirkwood and Austad. between the ages of 20 and 80 years there is a 90% loss of blood vessel distensibility. Pharmacokinetics All stages of the journey of a drug through the human body may be affected by aging. as cells age and loose the ability to divide. Many disturbances of old age have been linked to the occurrence of structurally modified proteins (Gafni. the responsiveness to and the serum levels of many hormones are decreased. 1998).. many theories have been proposed that can be generally divided into two categories.. 2003). which has long been considered to be beneficial. and other organ systems (Nelson. which together with enhanced intimal thickness and endothelial dysfunction appears to be responsible for the increase of systolic blood pressure and work load of the left ventricle. The mechanism of aging is unresolved. Lakatta and Levy. Activation of this enzyme has the same effect in fibroblasts (Troen. 2000). The notion that there is an internal clock or counting mechanism for cellular replication has gained interest from the observation that there is shortening of telomeres. 2002). cardiovascular. The stochastic theories stipulate that aging events such as damage of macromolecules by background radiation. growth. the elderly are increasingly prone to diseases and multimorbitity. the maximum O2 consumption declines. the most important pharmacokinetic change in the elderly being the reduction in renal drug elimination. 2003. 2003). 2003). normal human aging is associated with a reduction in baroreflexmediated heart rate response to hypotensive stimuli (Verhaeverbeke and Mets. 1997). a phenomenon termed ‘antagonistic pleiotropy’ (Kirkwood and Austad. . is beneficial in early life as it is important for bone formation.. that is a consequence of loss of myocytes with subsequent hypertrophy of the remaining cells. a syndrome that includes loss of skeletal muscle mass (sarcopenia) as well as neuroendocrine and immune dysfunctions (Walston and Fried. It appears that multiple genes influence the aging process. The replicative block that occurs in cells from patients with Werner’s syndrome also appears to be telomere-based. The increased stiffness of the left ventricle. 2003). also has a strong genetic component (Young and Smith. 2003). but the decline in functional reserve varies markedly between elderly persons (Lamy. the serum levels of estradiol and testosterone. Gabapentin and some nucleoside drugs are also absorbed by mediated transport. edrophonium. and valproate. opioids) retard intestinal absorption to a greater extent that does aging. equal doses as in younger individuals will result in higher plasma concentrations. the number of functioning glomeruli is reduced. total body water content falls by 10 – 15% until the age of 80. 2001). as drug elimination increases when the free (unbound) drug concentration is enhanced.1. increases from 18 to 36% in men and from 33 to 45% in women (Vestal. The volume of distribution of hydrophilic drugs therefore decreases. which in turn is dependent on the size of the hydrophilic and lipophilic spaces of the body. diazepam. The lean body mass. There is evidence that patients older than 56 years and afflicted with acute myeloid leukemia are more often positive for the multidrug resistance-associated protein-1 (mrd-1) than younger patients. it takes longer in these cases until a drug effect can be evaluated. the relative change in the volume of distribution for lipophilic drugs is more marked in men than in women. 1998). but it is unclear if their absorption is retarded in old age (Turnheim. the rate of transdermal drug absorption may be diminished in elderly because of reduced tissue blood perfusion (Trautinger. prazosine. Hence low bodyweight. famotidine. serum albumin can be quite low so that free drug concentrations may increase causing unexpected drug toxicity (Walter-Sack and Klotz. although the fat content is higher in women than in men. 1996). Compounds that permeate the intestinal epithelium by carrier-mediated transport mechanisms may be absorbed at a lower rate in the elderly. 1998). This finding has to be confirmed for other malignomas. a higher volume of distribution implies an increase in half-life and in the time necessary to reach the steady-state serum concentration during repeated drug administration. It should be remembered that the plasma half-life of a drug changes directly with its volume of distribution. This. examples are calcium. A decrease in plasma protein binding may therefore obscure an age-related decrease in drug clearance (Turnheim. 3. An important mechanism for removing drugs from the intracellular space is the P-glycoprotein transporter. but also ethanol (Turnheim.2. etomidate. diflunisal. 1997). are either increased or unchanged. teicoplanin. benazeprilat.. 1998). for instance. gut motor function. which binds primarily alkaline drugs. Total body fat. iron. Drug absorption Although the overall surface of the intestinal epithelium. the age-dependent changes in plasma protein binding are not clinically relevant. 1998). Agents that impede propulsive gut motility (antimuscarinic drugs. In malnourished patients with advanced cancer. is the case for aspirin. antihistamines. especially the skeletal muscle mass. lithium. Intramuscular injections should be avoided generally in this age group because of erratic absorption and the high risk of sterile infiltrates. Renal drug excretion After the age of 40 there is progressive development of glomerulosclerosis in the kidney. splanchnic blood flow and possibly gastric acid secretion decrease with age. Renal blood flow decreases by approximately 1% per year. These changes are attributed predominantly to renal or hepatic dysfunctions (Grandison and Boudinot. 1999). clomethiazole.. naproxen. Therefore.K. enalaprilat. Glomerular filtration rate declines by 25 – 50% between the ages of 20 and 90. Turnheim / Experimental Gerontology 38 (2003) 843–853 845 3. Small reductions in plasma protein binding in the elderly have been observed with acetazolamide. the expression of which is associated with multidrug resistance (Robert. The frailty of very old individuals tends to be overlooked. 3. and verapamil (Turnheim. 2000). 2002). Drugs in blood may be bound to plasma proteins with only the unbound fraction being pharmacologically active. among other factors increased angiotensin-II and endothelin levels and decreased prostaglandin concentrations may contribute to this effect. digoxin). Thus. Very old individuals loose weight and become frail. theophylline. Plasma albumin levels are decreased somewhat in the elderly. low weight patients on average receive higher doses per unit bodyweight than heavier patients. Examples for drugs with increased volumes of distribution in old age are amiodarone. tubocurarine. This holds also true for absorption from the subcutaneous and muscular tissue. 1987). so that . tricyclic antidepressants. Use of diuretics may reduce the extracellular space even further. An agedependent reduction of the extent or rate of absorption was shown for only a few drugs (indomethacin. the proportion of fat decreases so that the volume of distribution for lipophilic drugs again decreases and the serum concentrations increase. in addition to advanced age. salicylic acid. leading to accentuation of toxic drug effects. on the other hand. In other words. Tubular secretion falls in proportion to the loss of glomeruli. diazepam. Although there is atrophy of the epidermis and dermis in the aged with a reduction in barrier function of the skin. In general. the concentrations of a1-glycoprotein. Drug distribution The plasma concentration of a drug is inversely related to its volume of distribution. absorption of most drugs that permeate the gastrointestinal epithelium by diffusion is not diminished in the elderly.3. declines with age. Mdr-1 gene expression and age are the strongest predictors for failure of cytotoxic treatment (Schaich et al. and vitamins. constitutes a risk factor for overmedication (Campion et al. Thus far. 1974.. the reduction in renal drug excretion in old age can be compensated by correcting the maintenance dose. but dosing guidelines . no consistent relationship has been found between age and the activity of microsomal cytochrome P450 enzymes (CYP) that are responsible for phase-I metabolism (Le Couteur and McLean. lipids. 1999). 1998). the activities of glutathione transferase and UDP glucuronyltransferase are not altered (Le Couteur and McLean. Renal elimination of most drugs is closely correlated with the endogenous creatinine clearance. i. Turnheim / Experimental Gerontology 38 (2003) 843–853 the glomerulotubular balance is preserved (Lindeman. Drug metabolism Despite significant research efforts. 1995. no effect of age on the frequency distribution of slow and rapid metabolizers. the effect of age on hepatic drug metabolism continues to be a controversial issue. ¨ 1995. 1997). 1998). Hemoperfusion of the liver declines in elderly. ¨ Muhlberg and Platt. the prevalence of genetic polymorphisms. drug where Q0 . by the factor Q : D0m ¼ Dm k0e =ke ¼ Dm Q. But routine clinical tests of liver function do not change significantly with advancing age. ð1Þ where ke is the elimination rate constant. 1975). on the other hand. the endoplasmic reticulum is diminished. 2003). Under in vivo conditions. an average estimate of this parameter as a function of age and serum creatinine concentration. for instance antipyrine and theophylline (Table 2). In frail elderly. the interindividual variation in metabolic drug clearance by CYP enzymes or phase-I reactions exceeds the decline caused by aging. If CL0CR of an individual elderly patient is not available. Dm . The metabolic clearance of drugs with low hepatic extraction. Although the Cockroft and Gault equation is reported to overestimate the glomerular filtration rate and modifications have been published (Oo and Liu. an age-dependent decline of total clearance is to be expected for all drugs that are predominantly eliminated by the kidneys.85 to account for the lower skeletal muscle mass in women. Alternatively Q can be obtained from convenient nomograms that relate CLCR and Q0 (Dettli. is in most cases not reduced. 1999). drugs exhibiting high extraction therefore display an agerelated decrease in metabolic clearance as blood which flows through the liver is more or less completely ‘cleared’ from these compounds. 2000). 1991). Durnas et al. In fact.e. This type of metabolic clearance is termed ‘capacity-limited’ (Le Couteur and McLean. In vitro. although the serum albumin concentration may decrease slightly (Schmucker. CLCR . 3. Disregarding the reduction in drug elimination by the kidneys in the elderly will result in increased drug serum levels.. that for women is obtained by multiplication with 0. therefore the individual dose adjustment factor Q can be calculated from: Q ¼ Q0 þ ð1 2 Q0 Þ CL0CR . The reduction in liver size in old age is of the order of 25 –35%. Liver blood flow declines by about 40%. CLCR ð2Þ based on the creatinine clearance are often neglected in elderly patients (Papaioannou et al. The fundamental importance of kidney function for drug elimination is generally recognized. and glucose. apparently irrespective of which CYP enzyme is involved (Table 1). 1998). Values for Q0 can be found in appropriate reference handbooks (for instance Dettli (1996) and Fichtl (2001)). Whether the metabolic clearance of a drug is decreased or unchanged in old age has been attributed to the property of high or low extraction of the drug by the liver. The prime. Hence we speak of ‘blood flow-limited’ metabolism in these cases (Table 2). CCL (in mg/dl). 2002). Because of these changes. whereas that of others is unchanged. may be obtained from the equation of Cockroft and Gault (1976): CL0CR ¼ ð140 2 ageÞ·bodyweightðkgÞ : 72·CCR ð3Þ This equation gives a value for the creatinine clearance in men. 1990. represents the Q-value for anuric patients (Turnheim. has been identified (Vestal. the hepatic extracellular space increases. There are reports that the progression of kidney damage in old age may be retarded by angiotensin converting enzyme (ACE) inhibitors (Ferder et al. In general. Le Couteur and McLean. on the other hand. Muhlberg and Platt. Phase-II or conjugation reactions usually are unchanged in old age. since it is not dependent on hepatic blood flow but on the total tissue content of metabolizing enzymes (‘intrinsic clearance’). For drugs with linear pharmacokinetics. the extrarenal elimination fraction. for routine clinical use the Cockroft and Gault equation is practical and user friendly. bile flow is reduced as is the rate of synthesis of proteins. Spring.. However. The nutritional status of a patient has a marked effect on the rate of drug metabolism. changes in hepatic blood flow and intrinsic clearance do not provide a satisfactory explanation for the age-dependent reduction of hepatic metabolism of all drugs in the elderly. 0 designates the values in old age. Hence serum creatinine concentration may not change although the glomerular filtration rate is decreased. the decline in renal function is closely related to the incidence of adverse drug reactions (Lindeman. 1985.846 K.4. the metabolic clearance of some drugs is decreased by 20 –40%. 1998). It should be noted that judging renal function from the serum creatinine concentration alone can be misleading because the input of creatinine into the circulation is diminished in the elderly as muscle mass is reduced. sertraline (Turnheim. 2003). warfarin (Loebstein et al. and CL=f for a number of agents in old and young adults have been published previously (Turnheim. risperidone (Turnheim... 1994).. 1998). the individual clearance of a drug can be obtained form the steady-state drug serum concentration.. 2001) 847 Table 2 Effect of age on ‘blood flow-limited’ or ‘capacity-limited’ hepatic drug metabolism (data from Le Couteur and McLean (1998)) Metabolism in old age Reduced Unchanged CYP 3A4. (1) compensates only for altered ke : Using mean clearance values for the calculation of dosage with Eq. fentanyl. whereas Eq. 3A5 Alfentanil. 1998). the ability of the cells to respond to receptor occupation (signal transduction). venlafaxin (DeVane and Pollock. 1996. diclofenac (Brenner et al. 1998). (4) will give average adjustments. 2002). ropinirole (Kaye and Nicholls.. Glucuronidation Acetylation Glutathion conjugation metabolism is diminished to a greater extent than in elderly with normal body weight (Walter-Sack and Klotz. 1991). 1990) where f is the drug bioavailability and CL the total clearance that is equivalent to V·ke : Average values for f . diazepam.K. and on counterregulatory processes that tend to preserve the original functional equilibrium. verapamil Capacity-limited Antipyrine (phenazone). phenytoin (Durnas et al. Salicylic acid 1990) (LeCouteur and McLean. triazolam (Turnheim. 1990) Fluoxetin (Altamura et al. 1994). Vestal. Diazepam. Indicated are also the major enzymes or reactions responsible for a drug’s metabolism Metabolizing Metabolic clearance in old age enzyme or reaction Decreased Not changed CYP 1A2 Theophylline (Turnheim. propranolol (Colangelo et al. Turnheim / Experimental Gerontology 38 (2003) 843–853 Table 1 Effect of age on the metabolic clearance of various drugs. nortriptylin (Jerling et al. Age-related changes in pharmacodynamics may occur at the receptor or signal-transduction level or homeostatic mechanisms may be attenuated. 1992).. 1998). It should be noted that Eq. lidocaine. nifedipin (Durnas et al.. in addition to pharmacokinetics. metabolism theophylline phenytoin. C ss : CL0 or CL0 =f 0 ¼ Dm 0 Css ð6Þ Various CYP where CL and CL=f stand for the clearance after intravenous or peroral drug administration. digitoxin. carbamazepin. 1998) Isoniazid (Durnas et al. 1993).. AUC 0 ð5Þ CYP 2C19 CYP 2D6 Imipramin (Sallee and Pollock. irbesartan (Marino and Vachharajani. The dose adjustment to account for a decline in metabolic clearance (or in total clearance in general) can be obtained from D0m ¼ Dm f CL0 .. Caffeine (Durnas et al. amitriptylin. pethidine. zolpidem (Salva and Costa. the magnitude of a drug effect depends on the number of receptors in the target organ. morphine. 1999) Antipyrine (phenazone). Individual dosages can be obtained from the clearance in a given patient by measuring the area under the plasma concentration –time curve (AUC) and using the equation CL0 or CL0 =f 0 ¼ D . warfarin CYP 2C9 Celecoxib. imipramine.. salicylic acid. Alternatively. 2000) Amiodarone. imipramine. 1990) Turgeon. citalopram (Gutierrez and Abramowitz. (4) takes into account age-dependent changes of V and f in addition to ke . An increase in drug sensitivity has to be assumed when the response to a given serum concentration is enhanced. the pharmacodynamics of a drug may be altered in the elderly. 1990). 1990). 1999) Morphine (Durnas et al. propranolol. 1998).. 1990) where D is the dose administered. 1997). 1990). 1998). paracetamol (acetaminophen) (Durnas et al. metabolism lidocaine. pethidine. ibuprofen (Turnheim. valproic acid. Pharmacodynamics The pharmacokinetic guidelines for dose adjustment in the elderly given above disregard changes in the sensitivity to an agent. ke . Thus. 1990) Paracetamol (Durnas et al. verapamil ´ mexiletin (Labbe and (Durnas et al. 1990) Blood flow-limited Amitriptylin. Aside from its concentration at the site of action. 4. cyclosporine (Fahr. diltiazem. felodipin (Dunselman and Edgar. f 0 CL ð4Þ . 1995) Naproxen (Durnas et al. clomethiazole. V.. 2000)... Drug-induced orthostatic reactions. contribute to the risk of syncope and falls. that are thought to be involved in cognitive functions. Combined with the decrease in thirst. particularly those with evidence of target organ damage (Duggan. on the other hand. 1998. is also reduced as is the activity of heart muscarinic receptors ¨ (Hammerlein et al. On the other hand. In addition. hypovolemia may contribute to deficits in hemoperfusion of vital organs (Vestal. The intensity of the diuretic effect of these agents is therefore not primarily related to their concentration in plasma but to that in the lumen of the tubule. irrespective of age (. The number of cholinergic neurons and receptors. more time is required to regain the original steady-state as counterregulatory measures are reduced. 1998). hyponatremia. the reactions may be stronger than in young individuals and the incidence of adverse drug effects is higher. 1990. Because of a decrease in total body water with advancing age.. Diuretic therapy in the elderly is also complicated by the fact that the site of action of both loop and thiazide diuretics is the luminal cell membrane of the renal tubule. Hopefully the ‘Hypertension in the Very Elderly Trial’ (HYVET) and similar studies that are presently conducted (Zannad. ACE-inhibitors appear to be of benefit even in cases with perceived contraindications (Ahmed et al. The concentration-response relation of heparin. an equal volume of fluid loss in young and old patients represents more severe dehydration in the elderly. Turnheim. 1997). responses to nitrates do not appear to change with age (Verhaeverbeke and Mets. Turnheim. Digoxin is recommended in patients with heart failure not adequately responsive to ACE-inhibitors and diuretics. The increased risk of digoxin toxicity in old patients can be primarily attributed to reduced renal excretion (Hanratty et al. 1997). drug effects are attenuated less in the elderly. The reduction of the renal clearance of loop and thiazide diuretics in the elderly results in higher plasma levels and systemic toxicity. Howes. despite the general decline in receptor number or responsiveness. Many elderly patients are on long-term therapy with diuretics. Muhlberg et al. 2000) will clarify the riskbenefit relation of this treatment. was shown not to change (Turnheim. Apparently badrenoceptors are downregulated in old age by increased serum noradrenaline levels. Swift.. whereas the diuretic and natriuretic effect is decreased (Oberbauer et al. Eleven percent of cases of syncope in the elderly are reported to be drug-induced (Verhaeverbeke and Mets.848 K. In addition. even when adjusted for . the risk of bleeding is increased (Hylek.. Russmann et al. Do the aged benefit from antihypertensive therapy? At the present time. 2002).. The role of ACE-inhibitors in geriatric patients is debatable as renin secretion is decreased. the sensitivity of the myocardium to catecholamines is lower. 1998). and cardiovascular reflexes. 1997. According to the recently published ALLHAT study (2002). The decreased antihypertensive effect of b-adrenoceptor blockers may be related to the lower renin levels in the elderly. leading to extrapyramidal symptoms when a certain threshold of neuronal loss is reached (Wong et al. When assessing orthostatic hypotension in the elderly. fluid intake. Homeostatic mechanisms As mentioned. which mediate cardioprotective effects.. In contrast to effects mediated by b-adrenoceptors. 2000). Therefore. Receptor properties A reduction in response to b-adrenoceptor agonists has been reported for the elderly. especially when they are female. A typical example for the consequences of the decrease in homeostatic mechanisms is the increased susceptibility of elderly patients to postural hypotension in response to drugs that lower the arterial blood pressure (Turnheim. 1997). 4. and prerenal azotemia under treatment with thiazides in combination with loop diuretics ¨ is markedly higher than in younger patients (Horl.1. 2001. 2002). possibly because of diminished presynaptic a2-adrenoceptor activity and augmented noradrenaline release.. 2001). 1998). 2002). 1997). 2001). it would appear reasonable to treat elderly patients with hypertension.. 2002. The sensitivity of elderly patients to the anticoagulant effect of coumarines is higher than in younger individuals. thiazide diuretics are superior to calcium channel blockers and ACE inhibitors with respect to prevention of cardiovascular complications in hypertensive patients.2. 2003). But untreated. and in cases with atrial fibrillation and ventricular tachycardia (Ahmed. The age-related decrease in glucose tolerance appears to be a consequence of reduced insulin secretion and insulin sensitivity (insulin resistance). or $ than 65 years). ¨ 1995. is also decreased. to develop hypokalemia. 1998). the risk of patients over 65 years of age.. one of the fundamental characteristics of aging is a progressive reduction in homeostatic mechanisms. Turnheim / Experimental Gerontology 38 (2003) 843–853 4. 1998). Hence. peripherally acting antihypertensives such as calcium-channel blockers or loop diuretics may by associated with lower intellectual scores in the elderly (Turnheim. Responsiveness of adenosine A1receptors. 1997). elevated blood pressure may also be associated with cognitive impairment (Amenta et al. drug treatment should always be reviewed. But doubts remain regarding the benefits of antihypertensive therapy in the elderly. In the central nervous system the number of dopaminergic neurons and dopamine D2 receptors decreases in the elderly. that are estimated to occur at a frequency of 5 – 33% in geriatric patients. The decrease in cell proliferation in old age may be attributed to defects in growth factor receptor and signal transduction mechanism (Obeid and Venable. following a pharmacological perturbation of a physiological function. frequently there is oversedation. 2001). hence dosage should be primarily adjusted by clinical symptoms. 2002). The dosage of phenytoin is generally complicated because of its non-linear pharmacokinetic behavior (Bachmann and Belloto. pain may lead to depression and reduce the activities of daily living. Turnheim. Care has to be exercised with opioids as the response to conventional doses may be increased in the elderly. 1999). 2002). withdrawal symptoms include tremor. but gastrointestinal complications are half as frequent (Bombardier. brain weight is reduced by 20% and neuronal loss has been reported for several brain regions. and seizures. Possibly these alterations are responsible for the high sensitivity of elderly patients to benzodiazepines. 2002). Similarly. Meprobamate is highly addictive. The prevalence and severity of renal side effects observed with the classical NSAID and the COX-2 inhibitors are equal (Harris. Between the age of 20 and 80 years.. Hetzel. not by target plasma levels established for therapeutic drug monitoring in young individuals (Willmore. Tallis et al. advanced age is a risk factor for hypoglycemia caused by sulfonylureas (Turnheim. The prevalence for pain increases with advancing age. 1997. but in addition there may be confusion. and anticonvulsants. for instance midazolam (Klotz. The hematological toxicity of these compounds is increased as are the adverse effects on the gastrointestinal tract. shortacting benzodiazepines such as triazolam and oxazepam are to be preferred (Kompoliti and Goetz. The cell density of the bone marrow decreases and cell proliferation is curtailed in the elderly. . Benzodiazepines may cause impairment of short-term memory and contribute to subtle cognitive disturbances in the aged... Many elderly are dependent on benzodiazepines. and ultimately delirium. more atypical effects such as cognitive deficits are observed in geriatric patients. 1998. 1997).. Turnheim. insomnia. 1998). Ikegami et al. 1998). and the nervous system (Vestal. 1996. whereas they are usually irrelevant in young adults. 2002). Plasma concentrations required for young adults may be toxic for the elderly. hence these patients are particularly sensitive to the adverse effects of anticancer drugs. 1995). Intellectual functions are not only diminished by benzodiazepines but also by antidepressants. 1998). 1998). the cardiac symptoms caused for example by intravenous administration of carbamazepine and phenytoin may be life-threatening in the elderly. Turnheim. The American Geriatrics Society has endorsed the use of COX-2 inhibitors for management of persistent pain in older persons (Eitorial.K. the heart. 1999). 1998). Turnheim / Experimental Gerontology 38 (2003) 843–853 849 increased obesity and physical inactivity that are usually associated with old age (Muller et al. weak and strong opioids in sequential order with tricyclic antidepressants and antiepileptics as adjuvants (Davis and Srivastava. When poorly controlled. 2003). it should not be used in old individuals (Beers. agitation. 1995. Most importantly. Should treatment with these agents be absolutely necessary. 2002). The frequency of adverse effects of non-steroidal antiinflammatory drugs (NSAID) on the gastrointestinal tract and the kidney increases with age. they may react with symptoms such as agitation. Marked changes in brain phospholipid composition take place with increasing age that also involve the second messenger diacylglycerol (Giusto et al. It is advised to reduce the initial dose of antiepileptic drugs by 50% in geriatric patients. The agerelated reduction in dopamine content predisposes to an increased frequency and severity of extrapyramidal symptoms in response to dopaminergic blockade by neuroleptics and metoclopramide. The prescription of psychotropic drugs is disproportionally high and frequently inappropriate in the elderly. respiratory depression. The gray matter decreases continuously in volume with age. confusion. and a reduction of protective reflexes (Turnheim. 1998). the reduction in acetylcholine content renders old individuals more susceptible to the anticholinergic effects of neuroleptics and tricyclic antidepressants (Kompoliti and Goetz. 1998). 3 – 4% of elderly patients treated with NSAID experience bleeding from the intestine compared with about 1% in younger subjects (AGS Panel on Chronic Pain in Older Persons. Age-dependent changes in the GABAA-benzodiazepine receptor complex were shown not only in number but also in subunit composition. and immobility. the number of synapses decreases (Katzman. 2002). 1997).. neuroleptics. impairment of attention and memory. 1997. In addition. Wolfe et al. Selective serotonin reuptake inhibitors (SSRI) do not have significant anticholinergic effects. The potential for adverse reactions is also increased with antiepileptic drugs. This problem appears to be especially acute in nursing homes. hence these drugs should be the first-choice antidepressants in the elderly (Kompoliti and Goetz. As mentioned above. the white matter remains relatively unchanged.. Pain management in the aged should follow the WHO three-step scheme using nonopioid analgesics. the antimuscarinic effects of tricyclic antidepressants are augmented in older individuals. ataxia. 1998. Because of an impairment of glucose counterregulation in the elderly. Not only is sedation accentuated. and Parkinson syndrome is observed in geriatric patients on long-term antipsychotic therapy. akathisia. The recently developed selective inhibitors of cyclooxygenase (COX)-2 have analgesic and anti-inflammatory properties comparable to the classical nonselective NSAID. A high incidence of tardive dyskinesia. 1998. The central nervous system is a particularly vulnerable drug target in the elderly. Frequently neuroleptics are given for nonpsychotic behavioral and psychological symptoms (Ruths et al. The properties of a number of individual cytostatic drugs in elderly individuals have been described elsewhere (Skirvin and Lichtman. The hematological toxicity of these agents is increased in old age as well. Olshansky et al. growth hormone. no such progress is in sight (Holden.. 1998). motor incoordination and gait irregularities as well as cardiac arrhythmias.. Other interventions await testing in humans. droperidol. Old age. and ticlopidine. including osteoporosis treatments with calcium. Hylek. Nevertheless. the high number of medications used in this population. rather the dose has to be determined individually considering particularly the reduction in body weight 5. secondary prevention of hip fractures. 2002). Therefore there are no simple rules for prescribing that can apply to the entire elderly population. Sloane et al. meprobamate. But it is important to recognize the heterogeneity of drug response in the elderly. and clozapine have no or only a negligible effect on the QT-interval. melatonin. 2000). Turnheim.. 1998). and age-associated changes in pharmacokinetic and pharmacodynamic properties. Between 3 and 25% of prescriptions to elderly persons were classified as inappropriate (Spore et al. But the clinical studies concerning the effects of antioxidants on aging have been inconclusive. General Accounting Office. Turnheim / Experimental Gerontology 38 (2003) 843–853 Other drugs with antimuscarinic activity are phenothiazines and butyrophenones. St Johns wort. 6. However... In short. 2002). and multiple drug use are risk factors for these effects (De Ponti et al. 2000). Wilkinson et al. stop. and falls (Agostini and Tinetti. 2001. Changes in patient medical status over time can cause long-term drug therapy to become unsafe or ineffective. or even reverse the aging process. In some cases these products may even be harmful (U. 2002). 2002). Of interest is the observation that life is prolonged in mice and rats with caloric restriction. clearly the use of CNS-active medication in the elderly should be curtailed as much as possible. is underutilized in geriatric patients (Kamel and Duthie. presumably in part by delaying the occurrence of agerelated diseases (Masoro. including amitriptylin. quetiapine. 2002). But in spite of considerable hype to the contrary. imipramin... Sloane et al. Some of these compounds may give rise to global cognitive deficits. ginko biloba. 1995. histamine H1-receptor antagonists. Individuals that sustain a hip fracture are at a greater risk of acquiring another. In addition.. there is no scientifically valid evidence that antiaging drugs presently on the market (ginseng. hormone and cell replacement therapies (including stem cells). propanthelin. The quality of drug treatment in the elderly appears to be generally questionable (Pittrow et al. Selection of medication is an important factor influencing the likelihood of adverse drug events. and maprotilin and the neuroleptics thioridazine. and conventional parasympatholytic agents such as atropine. experiments with laboratory animals indicate that it may be possible to alter the rate of aging or the maximal life expectancy. Turnheim.S. 2002). 2002). chlordiazepoxide. procain) can increase longevity (Platt. 2002... or other genetic manipulations (Butler et al. Consequently. 1999. the incidence of falls and injuries is increased both in community-dwelling older persons and those living in long-term care-facilities (Leipzig et al. doxepin. 1997. causing prolongation of the QT-interval in the electrocardiogram and possibly life-threatening ventricular tachyarrhythmia (‘torsade de points’). The drug doses that are usually prescribed for younger adults may be too high for old individuals. So far. 2002. advanced age is frequently considered an unpredictable risk factor for drug treatment. chondroitin sulfate. whereas the side effects of ¨ these agents are sizable (Droge. Because of these uncertainties. Ensrud et al. vitamin D. consequently the elderly may be denied adequate pharmacotherapy (Editorial.850 K.. As much as one fifth of all hospital admissions of older subjects are attributed to adverse drug effects that are often not recognized by these patients (Mannesse et al. The rate of adverse drug effects is estimated to be 2-3 times higher in older individuals than in adult patients younger than 30 years (Turnheim. belladonna alkaloids. and haloperidol may have adverse cardiac effects. 1990. 1993. fish oil. may increase life expectancy include interventions that reduce oxidative stress. Although there are some uncertainties concerning the association between drug use. 2002). 2001) and those selling them often misrepresent the science upon which the antiaging claim is based. a-methyldopa. illnesses. heart failure. Other strategies that . olanzapine. garlic. Beers (1997) published a list of ‘inappropriate medications’ which should be avoided in old individuals. telomerase activation. Antiaging or longevity medicine Antiaging is a hot subject these days and there is brisk commerce in remedies that claim to slow. Certain drugs are rarely if ever indicated for the elderly because safer and/or more effective alternatives exist. An increases in life expectancy beyond that seen in the past century will require insights into the mechanism of the aging process which could provide the basis for its pharmacological manipulation. bradycardia. DHEA. the antidepressants amitriptylin. and legitimate research is under way to develop drugs that have this effect. Conclusions Persons aged 65 or older are particularly susceptible to adverse drug reactions because of multimorbidity. 2002). SSRI antidepressants and the newer atypical neuroleptics risperidone. 2002). the uncritical use of sedative drugs appears to be an important cause for the increase in morbidity in old age. disopyramide. or bisphosphonates. pentazocine. This goal may be reached using drug preparations with retarded release or fixed drug combinations. Manowitz.E. Campion.M. A. therapeutic target concentrations are not established for this age group. 1998. assessment and management of pain in the elderly. Sims.H. J. Int. P. 201 –204. Blouin. West.V.M.. Campisi. Warner. N. the use of antimuscarinic agents can result in glaucoma. Med.L. Clin. Wright. Overmedication of low-weight elderly. 1996. especially when diuretic. Mayor. 51. J. 2003. Am.S. 2002. Sci. Clin..E. D. B. 50. Demographics. Arch. A once or twice daily drug administration is optimal. An evidence-based evaluation of the gastrointestinal safety of coxibes. Am. Olshansky. C. 13–21.. Mignini. Pharma-cokinet. Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Bombardier. It would be convenient to use therapeutic drug monitoring to adjust dosage in old patients.. F. The Colorado thyroid disease prevalence study. Is there an antiaging medicine? J. Benefits of treating hypertension in the elderly.J. Cusack.. T. U. A. Hepatic drug metabolism and aging. Dokumed AG. 1997.. Srivastava. Clin. B. W. The age-dependent pharmacological properties of the drugs prescribed for the elderly should be clear to the physician. aminoglycoside antibiotics.. 2000. M. Should age affect treatment decisions? Drugs Aging 18. A. Soc. C. 147–151. L. 38– 44. 57. Hence. Clin. Arch. References Agostini. 489–494. Pharmacokinet. P. Rothman. D. Adverse drug effects have to be considered when symptoms such as dehydration.. McNamara.J. 734–741. Dilger. Tinetti.. Herrlinger. 1974. 1999. K. F. Ridgway. K. 28.G. Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants.. Altamura.C..... Am.. Barlow. J. Dunselman. Soc. Am.N. Steinemtz. 147. Sci. 26. 38. Med. Pharmacokinet. ¨ Droge. A. 123–126. White.F... Age and propranolol stereoselective disposition in humans. Geriatr. E. 2003. 287. Hofmann.. Murdter. L. Fossel. Pharmacokinetic guidelines may be used to calculate doses that result in drug serum levels in the aged equivalent to younger adults. A. Jr. Montanaro.J. Beers. 635– 651. Rothman. D.... Harman.W. C. F. Med. therapeutic priorities have to be identified. F. Hormone replacement therapy in relation to breast cancer. R. 283 –292. Ahmed. J. Cockroft. 1744–1745.R. 2003. R. Clin. Soc. Poluzzi. J. 1531–1536. Arch. calcium-channel blockers. N. Ther. Recanatini....S.D.. 2003. and psychotropic drugs are administered to elderly patients. 2002. Drugs that impair cognitive functions may cause social isolation and withdrawal. and disopyramide may cause manifest cardiac failure. G. Chen.. Davis. in patients with peripheral vascular disease b-adrenergic blockers can precipitate claudicatio.H. 2002. (Ed. B333– B338. Explicit criteria for determining potentially inappropriate medication use by the elderly. C. Med. Rabbia. Wedlund. Clin. G. 359–389.. Soc.. Neurol.W. NSAID.L. Amenta. not epiphenomena. C. 288. Gault. . DeVane.. pp.M. Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. 1999. B.. Am. S.J. M.. Am.... Sektion Klinische Pharmakologie. 2002. Belloto. Prediction of creatinine-clearance from serum creatinine. 19. Cardiol. V. P.. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor of calcium channel blocker vs diuretic. R. P.I. S. 1994. 2002. Gerontol. W.E.. Weiss. Drugs an falls: rethinking the approach to medication risk in older adults. it may be difficult if not impossible to define such target concentrations for the elderly because of the marked interindividual variation in this segment of the population. H. and intravascular Xray contrast media may aggravate kidney damage. for instance b-adrenergic blockers. Perls.. however. C..A.. 1).J. 2002. 5– 11. E. confusion.R. The antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). Newcomb. J. Pollock. DeLong. Canaris. C. Ahmed. Sci. Drugs Aging 15. 945 –947.. S. Ammerican College of Cardiology/American Heart Association chronic heart failure evaluation and management guidelines: relevance to the geriatric patient. Assoc. Marx. AGS Panel on Chronic Pain in Older Persons. M. Voi. 2001. Gerontol. M. Int. J. Safety of non-antiarrhythmogenic drugs that prolong the QT interval or induce torsade de pointes.. N. Edgar. J. 23 –57.. 1987.. North Am. R. An update. 1331–1343. 31– 41.. S.V.... 526– 534.M. Pharmakokinetische Daten fur die Dosisanpassung. Protective effect of antihypertensive treatment on cognitive function in essential hypertension: analysis of published clinical data. 3D–9D. N. Brenner. ¨ Dettli. 2002. Individualization of drug dosage in patients with renal disease... Cavalli. As a matter of fact.J.H. Duggan. constipation or urinary retention. 1659– 1666.. syncope and falls occur. Veglio.. The management of chronic pain in older persons. 37. Int. Gerontol. Drug Safety 25..N. Colangelo.M. Exp. Basel. P.). DeMaria. J. 418 –430. Olins. J. Only basic diseases should to be treated. dementia or excitation... C.. Felodipine clinical pharmacokinetics. 203–204. 21.C. Med.A.. J. 2002. 2981–2997. M. postural hypotension. But this procedure neglects changes in sensitivity to drugs. 631–638. Allman. The list of medications should be reviewed critically and periodically.. Durnas.. M. 10). Geriatr. De Ponti.. In: ¨ Schweizerische Gesellschaft fur Pharmakologie und Toxikologie.. Pharmacol.. E. drugs no longer needed are to be discontinued. Pharmacokinetic considerations of antidepressant use in the elderly.. 89 (Suppl. Pharmacokinet. W.. Med. Clin..J. Tomassoni. Clinical pharmacokinetics of fluoxetine. T. It has to be realized that drugs may worsen the course of chronic diseases. 977 –985. 263–286. 50. Drugs Aging 20.. 1992.... Grundlagen der Arzneitherapie. J. 1976. The number of drugs administered simultaneously should be reduced as much as possible in geriatric patients. Reder. Geriatr. R. J.K.E. Am. Psychiatry 60 (Suppl. M. starting from a smaller initial dose than used in younger adults (for example 50%) the dose should be titrated to a clearly defined therapeutic response. 235–250.. 51.. Avorn. Geriatr. Nephron 15. Turnheim / Experimental Gerontology 38 (2003) 843–853 851 and renal elimination in a given patient. 157.P. J. F. A. 1990.. Bachmann. Kiefe. antihypertensive.R. U.T. 1991. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Dettli. Med. 58. M. Percudani. Assoc.. Differential kinetics of phenytoin in elderly patients. M. 46. E.. the need for pharmacotherapy has to be evaluated very restrictively. robust drug serum concentration—effect relations for the elderly are lacking. Moro.J. 2002. Survival benefits of angiotensin-converting enzyme inhibitors in older heart failure patients with perceived contraindications. Butler. A Biol.A. 42. Exp..... Klotz. J. Hence. J. Age-dependent changes of the kidneys: pharmacological implications. Platt. 50. 70. Drugs Aging 18. Krivanek. Wochenschr. Clin. 47.. W. Jr. The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study.. Harris. 2003.. 37. 599–610. 1999. Venable.. Harats. 139–146. 1513–1523. Position statement on human aging. Ther. 2001. ¨ Muhlberg. E. 50 (Suppl. W. Vachharajani.. vol.E... Sect. 265–273.G. 1997. Aust. 57. F. Pasquare. 1997. Oxford University Press. 1998. Multidrug resistance in oncology: diagnostic and therapeutic approaches.. J.M. Differential pharmacokinetics of digoxin in elderly patients. R. 1993. Man In’t Veld. M.. (Ed. E.. M. Nicholls. Cardiovasc. 1470–1473. 1997.. Pharmacol. Arch.. R.. 1)... 1995–2000. D. Geriatr. Drugs Aging 19. 263– 276. Ferder. The underuse of therapy in the secondary prevention of hip fractures. J. Part I: Aging arteries: a set up for vascular disease.. Pharmacokinetic and pharmacodynamic changes in the elderly. Gilliland. Clin..852 K. Psychotropic drugs. 2002. Med. H. Pharmacokinet. 289 –298. Nelson. Pharmakokinetische Daten. Med. 2002.Y. G. Med. ¨ ¨ Russmann. Olshansky. J. Pharmacokinet.. Holden. How to induce severe electrolyte disturbances in the elderly? Wien... E. Trenk. 1995. Soc. Gerontol. L. 1–10. Gohlke-Barwolf. Salvador. H. Implications for therapy. 2000.). Halkin. D.. J..).. Change in creatinine clearance with advancing age. B. R. Soc. B. Wochenschr. 1997. 353– 362.. Nephrol. (Eds. R.und Pflegeheimbewohnern im Vergleich zu Patienten in ambulanter Pflege bzw. Boudinot. 365 –368.N. Kaye. A. Obeid.H.A.. Clarke. Interindividual variability in sensitivity to warfarin—nature or nurture? Clin. 359 –373. R. 39. Caloric restriction and aging: an update. Geriatr. 10D– 17D. 453 –462.. 535 –545. Baumgartner. 237–244. D.. Campbell. Pugh. Drugs Aging 17.J. Antikonvulsive Behandlung im hoheren Lebensalter— Grundlagen und Differentialindikation. Clin. N. J.M. 472–495. Basso. 233– 238.... 1995. ¨ Platt. 38. 960–968. Leipzig. M.F. Br. S. Am.G.J.F. Austad. Blackwell. Hyponatraemia and hypokalaemia caused by indapamide. Pharmacokinet. M. 2001.H.. D.. Circulation 1007. Arzneimittelanwendung bei Alten.G. Clin. Klotz.. S. Urban and ¨ Fischer.D. 885–886. D. Sci. H. Geriatr..J. Kamel. Henschler. B. F. A. 1–13. The aging liver.. C.. H. Grandison. 112 –122. Goetz. Lowenthal. Exp.J. J. Geriatr. S. T. (Ed. 2000. Clin.. Pharmacotherapy 20... Rotenberg...N. C. 1–2.. J. 1603–1604.. 11: Aging. M. P. J. J. Sect. 1996. Jungbrunnen oder Geschaft mit dem Alter? Verh. A. Robert.. Hanratty.. L. Loebstein. Geriatr. Am.M. Oo. Clin. 310 –318.P. Assessment of adherence to renal dosing guidelines in long-term care facilities. Exp. North Am. M. Katzman.. Kumahara.. 42–51.. Science 295. Fujisawa. Ensrud. Structural modifications of proteins during aging.. 159–164. Geriatr. 50. 35. Krappweis.J. Neuropharmacology in the elderly. 89 (Suppl. Roitelman. 35.. 2001. 1999. 2000... F. Mallet. Neurochem. Lakatta. 35 –39. Am.D. 2002. 27. G. Clinical implications of physiological changes in the aging heart. Pharmacol. Do doctors short-change old people? Lancet 342.. Passmore. Eur. Dtsch. Soc.T. N. 325–344.. Med. Effects of renin-angiotensin system blockade in the aging kidney.. O. 65.... H. 2001. Hofner. Effect of age on pharmacokinetics and pharmacodynamics in man. E.G. A Biol. Li. Mannesse. W.. T. McGlinchey. Jerling. H. Giusto.H. Geriatr. Inn. P.. Y. 127. Almog. Central nervous system active medications and risk for falls in older women... 11: Aging. T. W. K. Le Couteur.J... 1993. Mangione. The effect of age on insulin resistance and secretion: a review. Turnheim. Andres. Cardiol.. Geriatr. Mentre. The quest to reverse time’s toll. In: Masoro. K.M. Clin. Ezra. Handbook of Physiology. 1998.. Van Der Cammen. D.K. Drugs and falls in older people: a systematic review and meta-analysis: I. Wei. Soc.. Duthie.E. Ilincheta de Bosquero.J. Gerontol. Int... Spahn-Langguth. L. 299–305.B. Res. J... 2002. Pharmacol. A.. C. J. C.. A.E. A.H. Johnston.). 1999. New York. The management of persistent pain in older persons.R.... R. C. Lubetsky.. (Ed. W. Peleg. 871–880. Turgeon. Human nervous system. Abramowitz. S205–S224..J. Ther. Oral anticoagulants: pharmacological issues for the use in the elderly. Drugs Aging 1.. 30–39. Papaioannou. 1990. Med.C. 377–394. Derendorf. J. McLean... S. 96.. D. R. Age-related changes in protein binding of drugs. Pharmacokinet. Am. D. 243 –254. Inserra. 1991. Carnes. Oberbauer. D. J. W. Merle. Contribution of adverse drug reactions to hospital admission in older patients. S..M. Cumming. 36. Am. E. Tinetti.. Klin.G. 1994. J. Clinical implications. J.. Age-dependent differences in the anticoagulant effect of Editorial. Pharmacol... 1995. Bedard. 2002.. B.. Fichtl.D. Howes. Steady-state pharmacokinetics of citalopram in young and elderly subjects. Muller. 2000. 32. 361–384.. 114. P. Rosskamm.A.. Eitorial. K. E. K. 2002. 40. 485– 503. Lindeman. J.. 2000. D.J. 2002. 177. 16.. ¨ Muhlberg.. 45. Am. J.. Tobin. Clin.D.L. Age-associated changes in central nervous system glycerolipid composition and metabolism. Dtsch. 581–585. Ges. Kirkwood.. Ther. Masoro. 2002. pp. 361– 366. G. Fortschr.A. 2001..K. Fahr.. Arnold. 8. 1629–1637.. Sect. Clin. Jahnchen. 2000..I. C.G. A. Yonath. Oxford University Press.. Hylek. W. Soc. ohne Pflegebedarf. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Neurol.L. In: Masoro. Y. Elahi. E. 38. Renal and urinary tract. ¨ Horl. 6). T. Soc. 1999. U. Population pharmacokinetics of nortriptylin during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6—an evaluation with the nonparametric maximum likelihood method. L. Castagnet. Clin. 2002. M. Gerontology 45. Nippon Ronen Igakkai Zasshi 34.D. C.. K.. Cyclosporine clinical pharmacokinetics. Handbook of Physiology. 57. E. Clinical pharmacokinetics of mexiletine.. L. ¨ Hetzel.). W.. D. Ogihara. Am.K. Am..G. Turnheim / Experimental Gerontology 38 (2003) 843–853 ´ Labbe. Cyclooxygenase-2 inhibition and renal physiology. 1995. Samet. R. J. N. 29.. Ikegami. pp. Sem. Psychiatr. B292– B297. Kompoliti. Lamy. Pharmacokinet. 2002. 48. Why do we age? Nature 408. J. Levy. 45. New York. Kirch. 243 –253.. 261– 277. Munchen-Jena. 1998. 53–54. Hayflick.. 1441–1447. K. 2002. 11: Aging. 385 –404. Hormone replacement therapy and breast carcinoma risk in Hispanic and nonHispanic women. F. 16. Signal transduction in cellular senescence. M. Invest.. U. 2002. 95–109. Pharmacokinetics of irbesartan are not altered in special populations. Marino. 2000. D.L. C. Derkx. A. Geriatr.C. Pharmacol. 2000. In: Masoro... ¨ Hammerlein. Clin. 17. . Soc. Gafni... 1998.. Allgemeine und spezielle Pharmakologie und Toxikologie. The potential role of selected endocrine systems in aging process. Glucose tolerance and insulin resistance in the elderly.. De Ridder. Age Ageing 29. Gutierrez. Drug clearance and an oxygen diffusion barrier hypothesis.P. Pharmacokinetics and pharmacodynamics of the diuretic bumetanide in the elderly.M. 2003. Handbook of Physiology. Aufl. 34.. pp. R. J. Rakugi. In: Forth... Gerontol. Pharmacokinet. 271– 290. 1032–1233. H. Mutschler. Clinical pharmacokinetics of ropinirole. Neurol. 38. M. Clin. D. 2002. pp. Liu.M.. A. J.. ¨ Rummel. M.. 24.. H. E. Pittrow. Physiological changes due to age: pharmacodynamic changes of drug action and implications for therapy. Starke. F.. Forstermann.A. 1997.. A. P... T. 49 –64. Gerontol. Geriatrika-Altersbremse. Cancer 95. D. Straand. Pharmacokinet. . J. 50. S. Geriatrische Pharmakologie. Cancer 80.. U. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Frailty and the older man. Antiaging products pose potential for physical and economic harm. C. 1995. 349– 356. Drug dosage in the elderly. Soucek. 340. D2-like dopamine receptors: theory. Pharmacol. Clin. 1990. Gastrointestinal toxicity of nonsteroidal drugs. C. Exp. Pascheberg.. 401–413. Aging and pharmacology. Cereb... 1997. J. Clinical pharmacokinetics of imipramine and desimipramine. S19–S23.S. 1998. 2000. The effect of age on pharmacokinetics of antiepileptic drugs. 2002.K. Epigenetic aspects of cellular senescence. D. 357–379. 33–40.R. Skirvin. 26. Clin. 1990. North Am.. Ruths. 2002. T. Blood Flow Metab. J. Perucca. Larrat. Pharmacol. Washington.. S14–S21.. Biopharm. J. Wochenschr. P. Grubeck-Loebenstein. Mets.. 2002. 31. I... 1985. Fried. 25–42. 17.. 32. 46. 87–93. Lichtenstein. 52. J. Troen... Vestal. C. Bull. T. 57. Berger. 31–35.. Mor. B. 1997. T. Med. 1995.E. 1995. Wolfe... Turnheim / Experimental Gerontology 38 (2003) 843–853 phenprocoumon in patients after heart valve surgery. The biology of aging.. Am. Haematologica 87. L. Young.G. K. Pharmacodynamics: changes in homeostatic mechanisms. Costa. Smith. Problematik der Geriatrika und Nootropika. D.C. Inappropriate drug prescriptions for elderly residents of board and care facilities. 5). Clin.G. Ives. Sallee. B... Brubeck-Loebenstein. 1914.. Metzler.. D. Clin. S.. Drugs Aging 19. 3–22. M.F.. 142 –153. 1001–1011. J. Zimmerman.S. 29. Epileptic Disord.. Clin. Pharmacokinet. Aging and drug disposition: an update. D. General Accounting Office. Cardiovasc. Sinai J. Wick. Pharmacol. 70.D.. B. Wilson. 18.. Calculation of drug dosage regimens in patients with renal disease: a new nomographic method.. R. 2001. 455–464. Turnheim. Soc.J. U. 36 –52. 2002. J.. 1). Spore. 4 (Suppl. Eur. How well are community-living people treated for osteoporosis after hip fracture. Geriatr.A. Schmucker. B. receptor and target organ sensitivity in the elderly.. 1996... 105–118.C. Tallis. Pharmacol. Geriatr.. Trautinger.. Nygaard. Ehninger. E. Special Committee on Aging. Am. Epilepsy in elderly people: management issues. Mt..F. Gerontol. 76 –80.. 1997. Inappropriate medication prescribing in residential care-assisted living facilities.. Br. General Accounting office. 38. Rev. Clin. T.. Pharmacokinetic considerations of oral chemotherapy in elderly patients with cancer. 35 (Suppl. 2003. Swift.J. Gerontol. 1888–1899. 1997. Exp. Med. F.. J. Klotz. Willmore. Clin. 316– 330.L... 1999. M.. U. Clin. L. Eur.R. Brown. J.. Spring. 2003.. P. Gilchrist. K. Salva. 2001. Epilepsia 35 (Suppl. Pollock.P. 107. P. 1302– 1310. Sloane. Sainsbury. The potential advantages of a modern antihypertensive therapy in the elderly.. Hiris. 1173– 1194. 2001. Wilkinson. R. Association of specific cytogenetic aberrations with mdr1 gene expression in adult myeloid leukaemia and its implication for treatment outcome.. J. and changes during normal aging.D.. Dermatol. F. Drug Safety 17. P. 523–528.. 40. P. Engl. Eur. 404 –409. Pitfalls in pharmacokinetic dosage guidelines in renal insufficiency. Exp.J. Am. G. A. 83. Soc... 133–148. 50.M. N. Therapeutic implications.. Public Health 87.L. Wong... Verhaeverbeke. Influence of diet and nutritional status on drug metabolism. Pharmacokinet. Jansen-Durr.. J... U. P.. V. 2000. Singh. Illmer. J. G.A. Exp.R. 1997. Stephen.. 23–32. J. G. Clin. Schaich.. B. J. Med.. A Darwinian-evolutionary concept of age-related diseases. 346 –364. Gerontol. Pharmacol. Pharmakokinetik und Pharmakodynamik im Alter. Young. The aging immune system: primary and secondary alterations of immune reactivity in the elderly. Psychotropic drug use in nursing homes—diagnostic indications and variations between institutions. 47–64. validation.. Walston. 35.. Is it rational? Drugs Aging 13.. Walsh. 11.. J.. 853 Turnheim. 2).C. Gjedde. Quantification of neuroreceptors in the living human brain: III. Publication GAO-011129. L. 13–25.L. Avoiding its onset. 1975. L. P. J. Mechanisms of photodamage of the skin and its functional consequences for skin ageing. 1991. Pharmacol.. R. I.M. Turnheim. J. 1999. S. P. H. E. D. G. Med. K. Drug-induced orthostatic hypotension in the elderly. F.. 2002. Hawes. S. Klin. Mohr. N. 573–577. Lichtman. Int. Walter-Sack. Wien. ¨ Wick..R. Harbich-Brutscher. Boon. 37. J. Zannad.