SI Ankier

The pharmacokinetic and some pharmacodynamic characteristics of a single oral dose of 100 mg trazodone were compared in young and elderly volunteers. The maximum plasma concentration of trazodone was similar in both age groups. The time to maximum concentration was apparently prolonged in four subjects who swallowed the capsule with a minimal volume of fluid. This may have been due to the capsule being retained in the oesophagus. The terminal phase half-life of trazodone was significantly prolonged (P less than 0.05) and area under the plasma concentration-time curve was significantly larger (P less than 0.01) in the elderly. Apparent oral clearance was significantly reduced (P less than 0.01) in the elderly. Measurement of critical flicker fusion threshold and subjective assessment of alertness using a visual analogue scale, confirmed the sedative effect of trazodone in both age groups. The elderly subjects were less alert for a longer period following drug administration than the young. The differing pharmacokinetic and pharmacodynamic characteristics of trazodone in the young and elderly may be due to an age-related reduction in hepatic drug-metabolising activity, a difference in regional distribution or a change in CNS sensitivity to the drug.

1 A simple and specific procedure is described for the determination of the new anti-depressant trazodone in human plasma utilising reverse-phase HPLC which is sensitive to 20 ng ml-1. 2 Following oral administration of single 50 mg doses of two formulations of trazodone on separate occasions to healthy fasted volunteers, the peak plasma concentration, time to peak concentration, area under the curve, elimination rate constant and half-life were determined. 3 The two formulations are closely similar and they are considered to have comparable bioavailability.

The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers. No difference between the groups in peak plasma concentration (Cmax) or in the time to peak (tmax) was found, but the elimination half-life t1/2,z and area under the plasma concentration-time curve (AUC) were significantly greater in the elderly group. The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT] and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.

The pharmacodynamic effects of single doses of trazodone (100 mg), amitriptyline (50 mg) or placebo either alone or with ethanol (0.5 ml/kg) were investigated in six healthy volunteers in a double-blind crossover study. Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. Trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clear-headedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clear headedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks.

The effects of a new 1,4 benzodiazepine hypnotic, loprazolam (1.0 mg) and alcohol (0.7 g/kg body weight) were investigated over a 15 h period in eight healthy male medical students, in a placebo controlled balanced design. Loprazolam when given alone impaired performance on a manual dexterity task, on a test of mental arithmetic, on a tracking task and it impaired memory as judged by the name and address memory test. Given alone, alcohol impaired performance on the simple reaction time task and on the tracking task. Performance on the memory test and choice reaction time test actually improved. No evidence was found suggesting a potentiation of effect when loprazolam and alcohol were given together. However, (a) on the manual dexterity task the alcohol, having no effect on its own, alleviated the loprazolam-induced impairment. (b) In the tracking task both alcohol and loprazolam impaired performance when given alone but not when given together. (c) The memory test was impaired by loprazolam, improved by alcohol and the effect of the combination is the expected sum of the two effects. Similarly for the arithmetic task the effect of the combination of the alcohol and loprazolam effects is the expected sum of the independent effects. The bulk of the evidence on the interaction suggests that alcohol mitigates the effects of loprazolam. In no sense could the drug be said to be having a sobering influence.