Polypharmacy in the elderly from the clinical toxicologist perspective.

INTRODUCTION: Polypharmacy is closely associated with multimorbidity in the elderly and can lead to problems and drug interactions. AIM: This study assessed polypharmacy in the elderly, tracking inquiries to the Poison Information Centre Nuremberg (PICN) and patients needing toxicological intensive care therapy. METHODS: From 2006-2009, all PICN inquiries involving individuals > 70 years were tracked, as were cases at the Toxicological Intensive Care Unit (T-ICU) regarding adverse drug reactions (ADRs) and drug poisoning. RESULTS: Of 11,683 PICN calls about pharmaceuticals, 175 (1.5%) were from people > 70 years; 156 (4.8%) of 3,272 T-ICU patients were > 70 years. Calls about psychopharmaceuticals (46.9%) and analgesics (25.7%) were most frequent. Among the T-ICU patients, psychopharmaceuticals like sedatives and hypnotics were frequently involved (20.5%), as were tricyclic antidepressants (17.9%) and analgesics (29.5%). Ethanol was co-ingested by 18.3%. CONCLUSION: Population-specific poison prevention strategies are needed to reduce toxic exposures. Such strategies could include pharmacist intervention, improved prescriber communication and education regarding the geriatric population, and computerized drug databases.

Increased splanchnic arterial vascular resistance in oldest old patients - possible relevance for postprandial hypotension.

OBJECTIVES: The aim of this study was to evaluate possible age-related changes in mesenteric artery and portal venous blood flow dynamics in relation to systemic haemodynamics in order to delineate putative haemodynamic changes relevant for postprandial hypotension in the elderly. Studies were performed over a wide age-range and for the first time in over 85-year-old patients. DESIGN: Superior mesenteric artery (SMA) parameters (diameter, peak systolic velocity, end diastolic velocity, pulsatility index, volume flow) and portal vein (PV) parameters (diameter, portal vein velocity, volume flow) were measured by duplex ultrasound (General Electrics, Vivid 3) in 98 fasting subjects aged from 21 to 96 years. Systemic vascular parameters such as blood pressure, heart rate and cardiac output (echocardiography) were also determined. Excluded were patients with severe heart failure, liver cirrhosis, sepsis and those with mesenteric artery stenosis. RESULTS: Pulsatility index (PI) was positively correlated with age (r=0.33, p=0.015). In patients over 85 years, PI was significantly increased (p=0.002) as compared to younger controls. Cardiac output was negatively correlated with age (r=-0.247, p=0.005). The other haemodynamic parameters did not show age-dependent alterations. CONCLUSION: The increase of PI in the SMA in patients over 85 years represents an increase of vascular resistance in the splanchnic area, because PI is sensitive to resistance changes of small arterial vessels. The pulsatility index in the splanchnic area seems to rise steeply in oldest old patients, probably as an attempt to compensate diminutions in cardiac output seen in this age group. These findings indicate that the splanchnic vascular bed is already used in the fasting state to guarantee systemic haemodynamics. Vasodilatation of this vascular bed as physiologically seen postprandially may therefore easily induce postprandial hypotension in the oldest old.

[Fever in the elderly patient]. / Alter Mensch fiebert-- wann wird's riskant?

The multimorbid geriatric patient with age-related functional deficits is at particular risk from fever. Although the underlying cause is usually an infection, collagenosis, malignomas or drug-associated side effects all play an increasingly important role in patients of advanced age. In this segment of the population, the question of the reasonableness of a diagnostic work-up weighed against the expected improvement in quality of life is of particular relevance. The most common complication is dehydration, which may be followed by marked confusion. Account being taken of the requirements and the social situation of the individual concerned, any critical development should prompt early hospitalization, ideally in a geriatric hospital.

Comparison of the Mini Nutritional Assessment, Subjective Global Assessment, and Nutritional Risk Screening (NRS 2002) for nutritional screening and assessment in geriatric hospital patients.

The Mini Nutritional Assessment (MNA), the Subjective Global Assessment (SGA) and the Nutritional Risk Screening (NRS) are screening and assessment tools aimed at detecting malnourished individuals and those at risk for malnutrition. In our study we tested their applicability in geriatric hospital patients and compared the results of the three tools. We examined prospectively all patients of two acute geriatric wards by the MNA, the SGA and the NRS. 121 patients were included in the study. The MNA could be completed in 66.1% of all patients, the SGA in 99.2% and the NRS in 98.3%. There was a significant association of all three tools with the BMI (p<0.01). With regard to serum albumin and to length of hospital stay (p<0.05), only a significant association could be shown for the MNA (p<0.05). Although the categories of the results were not completely identical for the three tools there were more patients at risk or malnourished according to the MNA (70%) than according to the SGA (45%) or the NRS (40.3%). The direct comparison of the NRS with the MNA and the SGA demonstrated significant differences, especially for the latter (p<0.001). In a relevant percentage of those tested, MNA, SGA, and NRS identify different individuals as malnourished or at risk for malnutrition. Because of its association with relevant prognostic parameters, the MNA is still the first choice for geriatric hospital patients. For those patients to whom the MNA cannot be applied, the NRS is recommended.

Acute poisoning in old and very old patients: a longitudinal retrospective study of 5883 patients in a toxicological intensive care unit.

Although morbidity and mortality of acute poisoning are increased in elderly compared to younger patients, little has been published on this topics in the last years (Medline search). To investigate the influence of age on the clinical course of acute poisoning with different toxic agents, a longitudinal retrospective study at the Toxicological Intensive Care Unit (ICU) of the 2nd Department of Internal Medicine (Klinikum Nürnberg, Germany) was performed.A total of 5883 patients treated at our toxicological ICU were enrolled into the study, including all patients of the years 1982, 1992, and 1997. These three years were selected to investigate possible time-dependent changes of intoxication characteristics and quality of therapy at our ICU over a time span of 15 years. For each patient the following data were obtained from a standardized toxicological record: age, gender, toxic agents responsible for acute poisoning, and length of stay at the toxicological ICU. For a subgroup of 3740 patients, the cause of acute poisoning and the clinical outcome was also recorded. As compared with younger patients, mean length of stay at the ICU, indicating a more serious course of acute poisoning, was prolonged in elderly and, i. e., in very old patients (p <0.001). However, this prolongation of time at the ICU was only observed in elderly patients poisoned with drugs or with mixed poisoning including drugs, while mean length of stay was not prolonged in elderly patients poisoned with alcohol, with illegal drugs, chemicals, animal/plant poison, or other toxic agents. Patients with the highest risk of dying in the ICU after acute poisoning were elderly patients attempting suicide with drugs. Mortality in 3740 patients with acute poisoning was 0.24%, while it was 2.17% in the 184 patients being 65 years old or older. Thus, mortality was 9-fold higher in the elderly. Mean length of stay at the ICU decreased significantly from 1982 to 1992 and to 1997 (p <0.001) indicating an improvement of the therapeutical ICU management of acute poisoning and/or less dangerous toxic agents (i. e. less barbiturates). The age-dependent increase of the length of stay at the ICU until very old age (> 80 years) was most pronounced in 1982 and also declined markedly until 1997.Age, suicide attempt, and ingestion of (multiple) drugs seem to be risk factors for a higher mortality and a prolonged stay in the ICU after acute poisoning. Although in general the clinical course after poisoning has more complications and an impaired prognosis in old age, each category of toxic agents (drugs, alcohol, chemicals, etc.) has its own special "risk profile" for elderly patients. However, due to advances in modern ICU medicine the general prognosis of acute poisoning is good in old and even in oldest old patients.

Sarcopenia and frailty in geriatric patients: implications for training and prevention.

Sarcopenia, the loss of muscle mass and strength, is a constant phenomenon in aging. Physiologic age-dependent changes (drop in growth hormone (GH), IGF-1, menopause/andropause) explain the impaired protein synthesis, the decline of muscle mass, strength, and bone density. Harmful consequences of sarcopenia in old age are loss of muscle strength, inducing itself loss of mobility, neuromuscular impairment, and homeostatic balance failure syndrome with gait and balance disorders. All these sarcopenia-induced disabilities are important factors for an increased rate of falls and fractures in old age. Both falls and fractures cause hospitalisation and immobilisation which again induces sarcopenia. Once the physiological age-dependent decline of protein synthesis has started, some connected "vicious loops" occur in frail elderly patients, forming a typical pattern in geriatric medicine. There is a vicious loop between sarcopenia and immobilisation: sarcopenia --> neuromuscular impairment --> falls and fractures --> immobilisation --> sarcopenia. Another loop is the "nutritional" vicious loop between sarcopenia and malnutrition: sarcopenia --> immobilisation --> decline of nutrition skills ("empty refrigerator") --> malnutrition --> impaired protein synthesis --> sarcopenia. There is also a third "metabolic" vicious loop between sarcopenia and the decline of the protein reserve of the body: sarcopenia --> decline of the protein reserve of the body --> diminished capacity to meet the extra demand of protein synthesis associated with disease and injury --> sarcopenia. Frailty, a term not precisely defined, results from these different "vicious loops" including sarcopenia, neuromuscular impairment, falls and fractures, immobilisation, malnutrition, impaired protein synthesis, and decreased protein reserve of the body. Implications for training: main possibilities for training and prevention (of sarcopenia and frailty) are: a) continuous neuromuscular training (including training of balance) b) mobilisation c) prevention of falls d) training of nutrition skills and improvement of nutrition e) improvement of the impaired protein synthesis (with hormones etc.), and f) avoidance of dangerous drugs (drugs which cause neuromuscular impairment).

The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study.

Diuretics are a frequent cause of adverse drug effects in the elderly, many times involving drug-drug interactions. In addition, multiple chronic diseases, age-dependent pharmacokinetic and pharmacodynamic changes, and a decreased homeostatic capacity often complicate diuretic therapy in the elderly. The pharmacokinetics (area under the plasma concentration-time curve: AUC; peak concentration in plasma: c(max); time to reach peak concentration: t(max); terminal half-life: t(1/2)) and pharmacodynamics (urine flow rates and renal excretion rates of Na(+) at 1, 3, and 6 h after oral administration) of a fixed combination of 25 mg bemetizide and 50 mg triamterene were investigated in 15 elderly patients (age 70-84 years) and 10 young volunteers (age 18-30 years) after a single dose (day 1) and after multiple doses (at steady state, day 8). Compared with the young volunteers, mean plasma concentrations of bemetizide, triamterene, and the active triamterene metabolite were significantly higher in the elderly volunteers. These elevated plasma levels occurred after single dose and were even more pronounced after multiple dose in the elderly. While plasma concentrations and AUC of bemetizide, triamterene, and the active metabolite of triamterene were increasing in correlation to age of subjects and duration of therapy, urine flow and renal Na(+) excretion rates were decreasing at the same degree. At steady state conditions, practically no effect on urine flow and Na(+) excretion rates could be observed in the elderly patients (in contrast to the young volunteers) for the first 8 h after administration of bemetizide and triamterene. The lower the measured (endogenous) creatinine clearance was in all subjects, the higher were the plasma concentrations of bemetizide and triamterene, and the lower was the effect on pharmacodynamics (i.e. urine flow and renal Na(+) excretion rates). The glomerular filtration rate, known to be lower in the elderly (a priori), was apparently decreased at higher levels of bemetizide and triamterene in the elderly, which may explain why there was no diuretic and saluretic effect after multiple dose in the elderly patients.

Age-dependent changes of the kidneys: pharmacological implications.

About 40% of the intoxications after drug administration occur in the elderly. A significant proportion of the disease states in elderly patients is related to adverse reactions to prescribed drugs. Declining renal function, a reduction in both renal blood flow and glomerular filtration rate, is a major contributor to drug toxicity in the elderly. Therefore, a review (based on newer papers from Medline) of age-dependent changes of the kidneys and their consequences for drug therapy in geriatric patients is presented. Renal changes that occur with aging are: a decrease of renal weight, a thickening of the intrarenal vascular intima, sclerogenous changes of the glomeruli, and infiltration of chronic inflammatory cells and fibrosis in the stroma. Altered renal tubular function, including impaired handling of water, sodium, acid, and glucose, is also frequently present in old age. Impaired 'endocrinologic' functioning manifested by changes of the renin-angiotensin system, vitamin D metabolism, and antidiuretic hormone responsiveness has been reported. The aging kidney is constantly exposed to the effects of a variety of potential toxic processes, i.e., drugs and chronic illnesses including hypertension, diabetes, and atherosclerotic disease. Renal changes that occur with aging also consist of impairment in the ability to concentrate urine and to conserve sodium and water. These physiological changes increase the risks of volume depletion and prerenal type of acute renal failure. A frequent cause of acute renal failure in the elderly is drug-induced nephropathy. Nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics are most often involved. Due to the age-dependent decline of renal function, the pharmacokinetics of many drugs are altered in elderly patients. Therefore, the most important renal function to monitor with aging is the creatinine clearance. Changes in pharmacokinetics of many drugs and most decisions on drug dosage can be based on this information alone, as tubular functions of the kidney decrease at rates paralleling the age-dependent decrease in glomerular filtration rate (which is approximately measured by the creatinine clearance). As a conclusion, age-dependent changes of renal function are not only responsible for changes in pharmacokinetics and pharmacodynamics. In many cases, the kidneys are the target organ of adverse drug reactions too.

Pharmacokinetics of alprazolam in elderly patients with multiple diseases.

The pharmacokinetics of alprazolam (1 mg p.o.) were investigated (using a new developed HPLC-assay) in 10 multimorbid elderly patients (five female, five male; mean age 72.8 +/- 8.2 years, creatinine clearance 63.6 +/- 25.9 ml/min, weight 68.9 +/- 13.9 kg). Compared with young and elderly volunteers from other studies peak plasma concentrations of alprazolam were decreased while peak time and elimination half-life were increased. 'Second peak' plasma levels (correlated with age and creatinine clearance) occurred in eight of 10 elderly patients. The variability associated with the pharmacokinetic parameters in the multimorbid elderly patients was far greater than that observed in young and old healthy volunteers. Mean alprazolam concentrations in multimorbid patients aged 72 years or more were elevated as compared to 'younger' patients (age range: 63-71 years). Dose reduction should be considered in the older multimorbid patients.

The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients.

In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62-84 y, SBP greater than 160 mmHg, DBP greater than 100 mmHg, creatinine clearance 11-93 ml.min-1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0-24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol.l-1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.

Pharmacokinetics of diuretics in geriatric patients.

Pharmacokinetics of three diuretics (furosemide, spironolactone, and triamterene) were investigated in 70 geriatric patients. Comparing the data with the corresponding values of young healthy volunteers, mean plasma concentrations of furosemide and spironolactone (and peak concentrations of triamterene) were markedly higher in the geriatric patients. Different concomitant diuretic therapy (hydrochlorothiazide vs. piretanide) seems to influence the kinetic parameters of triamterene and its active metabolite in the geriatric patients. In elderly patients reduction or correction of the dosage seems to be necessary for all three diuretics investigated in our studies.

Pharmacokinetics of triamterene in geriatric patients--influence of piretanide and hydrochlorothiazide.

Pharmacokinetics of triamterene (single oral dose of 50 mg) and its pharmacologically active metabolite (OH-TA-ester) were determined in 20 geriatric patients with multiple diseases. Mean peak concentration of triamterene was increased in the elderly patients compared with the data of young healthy volunteers. Coadministration of piretanide seems to lower the mean plasma concentration (AUC) and the mean concentration after 24 h of triamterene as compared with the coadministration of hydrochlorothiazide.

[Pharmacokinetics and pharmacodynamics of theophylline in geriatric patients with multiple diseases]. / Pharmakokinetik und Pharmakodynamik von Theophyllin bei multimorbiden geriatrischen Patienten.

The pharmacokinetics of theophylline (200 mg i.v.) were determined in 20 geriatric patients with multiple diseases. Serum concentrations were fitted to an open 2-compartment model. Percent changes in venous pCO2 and pO2 were used as parameters of the pharmacodynamic action. Total clearance was decreased and elimination half-life of theophylline was found to be prolonged in the elderly patients compared with data of a study with young healthy volunteers. The stronger the pharmacodynamic action of theophylline (percent change of venous pCO2 after 30 min), the faster was its elimination and the lower were measured concentrations after 2, 6, and 12 h.

Pharmacokinetics and pharmacodynamics of furosemide in geriatric patients.

Twenty geriatric patients with multiple diseases were administered a single intravenous dose of 40 mg furosemide. Furosemide plasma and urine concentrations were measured using a thin-layer chromatography method and were fitted to an open 2-compartment model. Furosemide half-life was prolonged two-fold in the elderly patients compared with a control group of younger adults. In the same way renal clearance and total clearance were markedly reduced in the geriatric group. The non-renal clearance and the volume of distribution were not significantly altered. There were many significant correlations between clinical and biochemical data and pharmacokinetic parameters, especially between blood pressure and the area under the curve (AUC O-infinity), total clearance and non-renal clearance of furosemide. Our data suggest a special function of alpha-2-globulins in binding of furosemide. Renal function (i.e. creatinine clearance) was shown to be an important parameter for estimating the elimination rate of furosemide. In addition, pharmacodynamic action (volume of excreted urine) was closely correlated with the elimination rate: furosemide is apparently triggering its own elimination.

Serum level, half-life and apparent volume of distribution of doxycycline in geriatric patients.

The serum level, half-life and apparent volume of distribution of doxycycline were determined in geriatric patients. The serum level and apparent volume of distribution were higher than those reported for younger persons. The apparent volume of distribution was correlated with the serum iron and beta-globulin levels. The possible influence of binding of doxycycline to serum iron on its pharmacokinetics is discussed.