By H. Jick (auth.), E. Grundmann (eds.)
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26 These results are indirectly supported by a report of the Boston Collaborative Drug Surveillance Program (BCDSP) (1973a). 8% of 234 patients with a normal serum albumin, despite a similar average phenytOin dose in the two groups. The authors advanced the hypothesis that decreased binding of phenytoin to serum albumin was responsible for their findings, and a negative correlation between plasma albumin level and unbound fraction of phenytOin has been confirmed in a subsequent study (Porter and Layzer 1975).
In these conditions the rate of formation of the toxic precursor(s) exceeds the availability of reduced glutathione and cell necrosis occurs. Indeed, a positive correlation between the amount of cysteine and mercapturic acid conjugates in urine (expressed as a fraction of total metabolites recovered) and the severity of liver damage has been described in patients admitted to hospital after a paracetamol overdose (Davis et al. 1976). A mechanism similar to that discussed for paracetamol is probably responsible for the dose-dependent hepatotoxicity and nephrotoxicity of frusemide (Mitchell et al.
There is increasing evidence that the higher susceptibility of elderly patients to adverse drug reactions cannot solely be explained on the basis of pharmacokinetic differences such as impaired elimination or decreased plasma-protein binding. Bender (1964) has advocated the development in the elderly of an increased drug sensitivity at the receptor site. The adverse reactions to barbiturates so frequently observed in geriatric patients are likely to be due to this mechanism (O'Malley et al. 1976).