clinical pharmacology THE EFFECT OF AGE ON DRUG KINETICS

Atenolol kinetics are not significantly altered in advanced age Atenolol is a selective ~-adrenoceptor blocker which is eliminated mainly as unchanged drug by the kidney. Seven young male subjects (aged 23-32 years) and 7 elderly men (aged 66-78 years) were randomised to I OOmg of oral atenolol on I day and I Omg ofiV drug on another day. At least I week was allowed between the 2 doses. Mean atenolol clearance in the elderly men tended to be slower (163m!/ min) then in the younger subjects (203m!/ min). The volume of distribution at steady state (0. 7 5 vs 0.55Likg) tended to be greater, and the half-life ofiV drug (211 vs I 00 min), tended to be longer in the elderly. However, these differences were not statistically significant. The half-life of oral atenolol was significantly longer in elderly subjects (350 min) than in young subjects (282 min). The half-life of oral atenolol was 41-66% longer than the half-life of IV drug. This suggests that some atenolol may be eliminated by a dose-dependent non-glomerular pathway. The bioavailability of atenolol in both groups of subjects was 0.55-0.56. Mean creatinine clearance was estimated to be 63ml/min in elderly subjects and I 08m!/min in the young subjects. 'It can ... be inferred that the modest decline in renal function with age in individuals otherwise free of renal pathology is insufficient to alter the elimination of atenolol.' Rubin. P.C. et al.: British Journal of Oinical Pharmacology 13: 235 (Feb 1982)

The half-life of desalkylflurazepam is markedly longer in the elderly The kinetics of flurazepam were assessed after 26 healthy non-insomniac subjects were given a 15mg dose. During the first 6-8 hours after dosing, several flurazepam metabolites were observed by gas-liquid chromatography. However, after 12 hours only desalkylflurazepam (DAFLZ) was noted. The half-life of DAFLZ was longer in subjects aged 61 years and older (especially males) than in subjects less than 34 years old. The mean DAFLZ half-life was 7 4 hours in young men, 90 hours in young women, 160 hours in elderly men and 120 hours in elderly women. Peak plasma DAFLZ levels were similar in each group ( 1 0.2-14.5ng/ml), though they occurred much later in elderly men than young men (28.5 vs 4.1 hours). 18 subjects were then given flurazepam !Smg nightly for 15 consecutive nights. The accumulation half-life was longer in elderly subjects (I 04-1 15 hours) than in young subjects (74-89 hours). Elderly patients tended to have higher levels of unbound DAFLZ (3.7% vs 3.1-3.4% ), possibly owing to their lower serum albumin concentrations. Steady-state levels of unbound DAFLZ were significantly higher in elderly men than young men (3 vs 1.8ng/ml), as were mean total steady-state DAFLZ levels (81 vs 53 hours). However, total DAFLZ levels were the same in elderly and young women (85-86ng/ mO. Patients reported feeling greater morning sedation with continued nightly use offlurazepam. Sleep patterns improved on flurazepam therapy in all subjects, as indicated by shortened sleep latency, longer duration of sleep, and a 'deeper' sleep. Morning sedation gradually reverted to baseline within a week of stopping flurazepam. There was a suggestion of an 'overshoot' sleep disturbance 5 and 7 days after flurazepam withdrawal. Elderly subjects did not show increased sensitivity to flurazepam. No impairment of motor performance or intellectual function was noted by any subject. Greenblatt. D.J. et al.: Clinical Pharmacology and Therapeutics 30:475 (Oct 1981)

Theophylline doses need to be 39% lower in patients over 75 years old 69 patients (including 23 smokers) with chronic obstructive lung disease, were given oral microcrystalline theophylline therapy at doses calculated (by nomogram) to produce steady-state plasma theophylline trough levels of SOJ.lmol/L. The average regimen prescribed was I 0.57mg/kg/day in 3-4 divided doses. Patients older than 75 years required theophylline doses 39% lower than younger patients. Smokers received an average dose 43 % higher than that of non-smokers. 50.4 % of patients achieved trough levels between 40-60J.lmol/L, with I I % more smokers than non-smokers missing this range. 69% of patients having trough levels outside the 25-75J.lmoi/L range were smokers. 13% of patients had maximum theophylline levels over 85J.lmol/L which were associated with increased side effects. The study showed that the effect of advanced age on theophylline dose was greatest in patients older than 7 5 years. A theophylline dose of7.5mg/kg/ day would seem appropriate for a 75-year-old non-smoker. Talseth. T. et al.: Acta Medica Scandinavica 210: 489 (No 6. 1981)

Protein binding of quinidine reduced in the neonate 26 paediatric patients, comprising 6 neonates, 8 infants (age range 8-18 months) and 12 children (over 2 years), took part in a study designed to investigate age-related differences in the serum protein binding of quinidine. There was a significant decrease in the proportion of free, unbound serum quinidine (i.e., an increase in protein binding) with age. Serum quinidine was 60.8% protein-bound in neonates, 75.6% bound in infants, and 83.4% bound in children. Diminished protein binding of quinidine in the neonate and infant makes clinical toxicity with low to normal quinidine blood levels a possibility. Pickoff. A.S. et al.: Developmental Pharmacology and Therapeutics 3: I 08 (No 2. 1981)

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No age-related change in tobramycin pharmacokinetics 77 patients with normal renal function (25 in age group 20-39 years, 23 in age group 40-59 years, and 29 in age group 60-79 years) were given tobramycin for treatment of Gram-negative infections. 45% of patients required more than 5mg/kg/day (maximum recommended dose) to achieve the required steady-state levels. Mean values for tobramycin half-lives (2.2-2.4 hours) volumes of distribution (0.25-0.26L/kg) and clearances (1.25-1.44ml/min/kg) were similar in the 3 age groups, with no correlation between any parameter and age. Bauer. L.A. and Blouin. R.A.: Antimicrobial Agent' and Chemotherapy 20: 587 (Nov 1981)

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