The elderly are known to be more susceptible to adverse drug reactions. Age differences in pharmacokinetics (i.e., absorption, distribution, metabolism, and elimination) may contribute to an increased susceptibility of the elderly to both the therapeutic and toxic effects of some drugs. For many drugs studied, such pharmacokinetic differences are generally consistent with age differences in body composition, renal function, and protein binding. Ageing is associated with a decrease in lean body mass and total body water, and a decline in glomerular and tubular function in the kidney, and diminished cardiac output and liver blood flow. In addition to considering the epidemiology of adverse drug reactions and the altered physiology and pharmacokinetics in the elderly, this review attempts to provide an overview of what is known about the relationship between advanced age and the pharmacokinetics of some drugs mainly eliminated via the kidney. Thus, several methods are presented to permit rational dosage regimen modifications for elderly patients with diminished renal function. Based on a review of the accumulated literature related to clinical geriatric pharmacology, it is concluded that dosage regimen adjustments based on therapeutic drug monitoring are essential to make drug therapy in the elderly safer and more effective.

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Changes in the distribution and densities of muscarinic acetylcholine receptors (mACh-R) in young adult and aged rat brain, and the effects of chronic administration of lisuride hydrogen maleate (lisuride) on these changes were studied by in vitro quantitative autoradiography of [³H] quinuclidinyl benzilate binding. mACh-R was relatively higher in the striatum, hippocampus and cerebral cortex in the young adult rats. In contrast, mACh-R binding was markedly reduced in the striatum, accumbens nucleus, amygdaloid nucleus and frontal cerebral cortex of aged rats compared to young adult rats. However, chronic administration of lisuride significantly increased mACh-R binding in the parietal cerebral cortex as well as in the above-mentioned regions in aged rats. This lisuride-induced increase in mACh-R of aged rat brain is considered to have important implications concerning the mechanism of therapeutic efficacy of lisuride.

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The long-term efficacy and side effects of antiplatelet and anticoagulant therapy for secondary prevention after the first acute myocardial infarction (AMI) were retrospectively assessed in 133 patients over 60 years of age during a mean follow-up period of 36.6 months. Seventy five patients received antiplatelet and anticoagulant therapy (group 1) and 58 patients did not (group 2). In group 1 patients, 54, 12 and 9 patients received ticlopidine, aspirin and warfarin, respectively. Mean age, sex ratio, site of AMI, max CPK value and left ventricular ejection fraction in the convalescent phase did not differ between the two groups. There were no differences between the two groups in terms of the number and kind of combination drugs such as nitrate, beta-blocker and Ca antagonist. During the follow-up period 40 patients died; 18 patients (45%) suffered cardiac death and 22 patients (55%) experienced non-cardiac death. Nineteen patients had recurrent MI and 37 patients had cardiac events which were defined in total as cardiac death, recurrent MI and unstable angina pectoris. The total mortality rate and rate of recurrent MI based on the life time table method were significantly lower in group 1 than in group 2 by the generalized Wilcoxon test. The cumulative total mortality rate in the fifth year was 24.2% in group 1 and 49% in group 2. The cumulative rate for recurrent MI in the fifth year was 7.4% in group 1 and 27.5% in group 2 (p<0.05). However, the rate of cardiac events did not differ between the two groups. Ten patients (13%) in group 1 discontinued antiplatelet and anticoagulant therapy due to the complication such as bleeding tendency, gastrointestinal symptom and liver dysfunction. Thus, long-term antiplatelet and anticoagulant therapy was relatively safe and effective on secondary prevention for recurrent MI in aged patients with first AMI.

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Clinical characteristics were examined in 5 elderly patients whose brain showed typical features of Wernicke's encephalopathy at the autopsy. All 5 were females with a mean age of 67±4 years old. The pathological diagnosis of Wernicke's encephalopathy was based on the presence of bleeding or atrophy of bilateral mammilary bodies, proliferation of capillaries and increase of macrophages in mammilary bodies, midbrain periaqueductal gray matter and periventricular area, with relatively intact neurons. Wernicke's encephalopathy was diagnosed clinically only in one case. The remaining four had no clinical diagnosis of Wernicke's encephalopathy. Underlying diseases were varied including neurological, metabolic, gastrointestinal disorders and malignancy. The predominant symptom, consciousness disturbance, was seen in 4 cases. Two of them showed a comatous state. Ocular symptoms and ataxia were observed in 2 cases. Laboratory findings revealed leukocytosis and anemia in 3 cases, hypoproteinemia in 4 cases. One case was alcoholic, but the other four were non-alcoholics and developed the disease after prolonged malnutrition. At the onset of the disease, 4 cases were receiving glucose and electrolyte infusion without vitamins, at the onset of the disease. We propose that in elderly patients with consciousness disturbance of unknown cause, Wernicke's encephalopathy should be taken into consideration even in non-alcoholics, and thiamine infusion should be commenced at once when the disease is suspected even when typical symptoms are lacking.

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The purpose of this study is to clarify possible correlations between dementia and long term bedridden elderly patients in our special nursing home and geriatric hospital. At the time of our study, 42.6% of all our patients were bedridden, and the ratio increased in those groups of advanced age. The percentage of bedridden female patients was higher than that of males. Most bedridden patients, suffered disorders of the nervous system particulary disorders caused by cerebrovascular disease. Among the bedridden patients, the incidence of dementia was 82.8%. In most these cases, the degree of dementia was severe. The types and respective percentages of dementia were as follows: Vascular type 45.1%, Alzheimer's type 23.2%, mixed type 19.5% and others 12.2%. We think that Alzheimer's type dementia may cause a patient to become bedridden. On the other hand, vascular type dementia may be promoted by a patient's being bedridden for a long time. Tube-fed patients comprised 20% of all bedridden patients and all of these patients showed dementia. We believe that a patient's getting out of bed and receiving rehabilitation as soon as possible is vital to the prevention of becoming permanently bedridden. In respect to the present study of bedridden dementia patients, we would like to further study tube feeding and terminal care.

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From the viewpoint of the high frequency of mild hypothermia in patients with senile dementia, we investigated causative factors in comparison with accidental hypothermia. We also investigated the relationship between hypothermia and the type or grade of dementia. A total of 127 demented cases including 30males and 97 females, whose mean age was 80.6±8.9 years, were classified into 3 groups according to the axillar temperature measured in August 1989. Group A consisted of 33 cases whose body temperature was below 36°C on more than 25 days. Group C consisted of 24 cases whose body temperature was above 36°C on more than 25 days, and the remaining 70 cases were classified as group B. The frequency of group A classification in demented patients was higher than age-matched non-demented controls (26% vs 13%, p<0.05). In demented males, serum total cholesterol, serum albumin, and hemoglobin were significantly higher in group A than in group B or C. Body weight and serum triglyceride were also higher in group A, but not significantly. In demented females, serum albumin and hemoglobin were higher in groups A and B than group C. In addition, cases with diabetes mellitus or cases receiving with major tranquilizers were more frequent in group A, and the index of activities of daily living was higher in group A, in both sexes. Factors such as age, CRP or thyroid hormone (free T3, free T4) showed no significant difference among the 3 groups. In addition, there was no difference in the frequency of group A between degenerative dementia and vascular dementia, though Hachinski's ischemic score was higher in group C. Groups A and B had higher Mini-Mental State scores than group C, and the degree of brain atrophy calculated from CT was less in groups A and B than group C. The prognosis observed during 9 months showed higher mortality rate in group C than group A or B. These findings revealed that demented patients with mild hypothermia were in a better nutritional state and had better daily activity levels and prognoses. This fact suggests that mild hypothermia of demented patients had different pathophysiological aspects from accidental hypothermia. On the other hand, it was shown that patients with mild hypothermia seemed to have less advanced dementia. The possibility was discussed that body temperature in senile dementia may be affected not only by a nutritional state but also by other factors, including neurotransmitters in the brain.

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A 69-year-old female patient had been treated with glucocorticoid for eight years because of rheumatoid arthritis. She showed characteristic Cushingoid features such as central obesity, moon face, and fragility of skin and vessels. She was disabled because of spinal compression fracture and muscle weakness. The blood pressure was 186/100mmHg and the laboratory tests revealed serum K: 2.8mEq/l, WBC: 15, 510/mm³, total cholesterol: 310mg/dl. These suggested that she had iatrogenic Cushing's syndrome. After discontinuation of glucocorticoid, however, the serum cortisol level remained high. This fact prompted us to conduct further examinations for Cushing's syndrome. Oral dexamathasone administration did not suppress the plasma cortisol level and a left adrenal adenoma was found on abdominal CT scan. Because of the presence of bleeding diathesis, operation for adenoma was contraindicated. Though we tried to treat her with metyrapone, trilostane or opeprim (OP'-DDD), we had to abandon specific treatment because of severe side effects such as acute adrenal dysfunction and gastrointestinal problems. Decrease in the endogenous cortisol level after metyrapone treatment caused exacerbation of symptoms of rheumatoid arthritis. This is a peculiar case in which the longterm administration of glucocorticoid for rheumatoid arthritis might have concealed Cushing's syndrome, and conversely the increased intrinsic adrenal steroid hormone might have suppressed the activity of the rheumatoid arthritis.

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A 69-year-old male visited our clinic in 1973 because of atrial fibrillation noted during an annual check-up for the aged. Blood pressure, heart rate and CTR in chest X-ray films showed 110/80mmHg, 150/min and 55%, respectively. There were no signs of valvular heart diseases, and a diagnosis of lone atrial fibrillation was convincing. Since then, repeated ECGs recorded twice or more a year had shown atrial fibrillation until 1988, when sinus rhythm with both first degree AV block and low P-wave amplitude appeared. The motion pattern of the anterior mitral leaflet on M mode echocardiography was abnormal with almost complete disappearance of the A-wave, whereas the motion pattern of the tricuspid valve was normal.

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The authors report the successful control of labile hypertension associated with orthostatic hypotension in a 75-year-old male patient, by means of L-DOPS, a synthetic precursor of nerepinephrine in combination with antihypertensive drugs. He had been known to be hypertensive for 15 years and developed a persistent floating sensation 2 years age. Despite good control of hypertension after admission, orthostatic hypotension was still observed. Passive tilt produced a blood pressure reduction of 60/20mmHg. Spectral analysis of heart rate variability showed a disturbance in the activation of the sympathetic nervous system. Treatment with L-DOPS attenuated the blood pressure reduction in response to passive tilt (35/12mmHg) and improved the sympathetic response. Because of an increase in blood pressure by L-DOPS, addition of either a calcium channel blocker or an angiotensin-converting enzyme inhibitor was necessary. These combinations of treatment successfully controlled blood pressure as well as orthostatic hypotension.

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