No abstract

The effects of age and cigarette smoking on the disposition of propranolol have been investigated in 27 normal men, aged 21 to 73 yr. The drug was administered orally (80 mg) every 8 hr and 40 f.LCi intravenous 3H-propranolol were administered simultaneously with the seventh dose. Labeled and unlabeled propranolol concentrations were determined in serial blood samples obtained over the next 8 hr. Subgrouping the oral blood concentration/time data according to age (younger or older than 35 yr) showed that the mean levels in the older group were as much as twofold those in the younger group, and that the terminal half-life (t1f2{3) was prolonged with age (4.19 ± 1.38 vs. 5.05 ± 1.36 hr, mean ± SD; p = 0.03). Substratification of cigarette smokers (>10 cigarettes daily) from nonsmokers indicated that the mean levels in the nonsmokers were 200% higher but there was no tl/z{3 difference. Despite the considerable interindividual variability, there was a trend for the weight-normalized, average steady-state levels to be lower in smokers than in nonsmokers, with the difference becoming smaller with increasing age. Analysis of the data indicated that the intrinsic total clearance of propranolol decreased with age only in the smokers, and toward the constant value of the nonsmokers, while apparent liver blood flow declined equally with age in both groups. Consequently, systemic clearance correlated negatively with age in the smokers and in the group as a whole. No age relationships were found in the volume of distribution and, thus, correlations of age and tllz (3 were of the same order as those of systemic clearance. No changes were observed in systemic availability or plasma binding with aging in either group. It, therefore, appears that cigarette smoking habits are important in the altered steady-state kinetics of propranolol that develops with aging. The results are consistent with a decreased induction of drug-metabolizing enzyme with aging.

Propranolol disposition has been investigated in 15 normal subjects with the use of a protocol which allowed simultaneous determination of the kinetics of the drug after both intravenous and oral administration by giving H3‐propranolol intravenously and native drug orally. In addition, plasma propranolol binding and the bloodlplasma propranolol concentration ratio (B/P) were measured. The data were used to calculate hepatic blood flow as well as systemic drug clearance from the blood and intrinsic clearance, which is an estimate of the activity of the drug‐metabolizing enzymes. Under the steady‐state conditions used, the hepatic extraction ratio was found to be 64% ± 2.5% (mean ± SE) resulting in a bioavailability of 36% ± 2.6%. Calculated liver blood flow varied from 778 to 2,162 ml/min, and, as predicted, the systemic clearance of propranolol (0.61 to 1.52 L/min) was correlated with both liver blood flow and intrinsic drug clearance (1.16 to 5.08 L/min). Variations in plasma drug binding had no effect on systemic clearance. Because of presystemic or “first‐pass” elimination, the variation in both free and total propranolol levels was greater after oral (5‐fold) than intravenous administration (2.5‐fold). We conclude that the approach described allows quantification of all of the biological determinants of propranolol disposition in subjects with normal hepatic vasculature.

SUMMARY Theophylline is thought to act by inhibiting the activity of phosphodiesterase, with a resultant increase in intracellular cyclic AMP. However, this concept is largely based on in vitro studies using concentrations of theophylline which greatly exceed therapeutic plasma concentrations. To investigate the relationship of the cardiovascular and metabolic effects of theophylline to activation of the sympathetic nervous system, i.v. aminophylline was administered to six healthy males under basal conditions. Each subject received four infusions. Mean theophylline concentrations (±+ SEM) of 4.5 + 0.2, 10.0 0.5, 14.0 + 0.5 and 20.0 + 1.2 ,ug/ml were achieved. Plasma epinephrine increased 262% (from 29 4 to 105 14 pg/ml, p < 0.01) and plasma norepinephrine increased 64% (from 190 1 18 to 312 51 pglml, p < 0.05) during the high-dose infusion. The increases in circulating catecholamines were dose-related (p < 0.001 by analysis of variance). Dose-related increases in heart rate, systolic blood pressure, plasma glucose, free fatty acids and insulin were also observed (p < 0.001 by analysis of variance). Although the duration of total electromechanical systole (QS2) and left ventricular ejection time adjusted for heart rate fell during the aminophylline infusions, this positive inotropic response was not influenced by dose, except possibly the high dose. Echocardiographic ejection fraction was not changed by the aminophylline infusions. We conclude that the acute cardiovascular and metabolic effects of theophylline may be mediated in part by stimulation of the sympathetic nervous system. AMINOPHYLLINE (theophylline ethylenediamine) is a methylxanthine derivative that is widely used in the treatment of cardiovascular and respiratory disease. Although ethylenediamine has been implicated in allergic reactions to aminophylline, it is otherwise thought to be therapeutically inactive. Theophylline and other methylxanthines are known to exert a variety of important physiologic and biochemical effects. ' Although the dose-response relationship between plasma concentrations of theophylline and improvement of pulmonary function during bronchospasm is well established,2' I a similar relationship for its cardiovascular and metabolic effects has only recently been examined in human studies." Despite the evidence that the acute administration of methylxanthine derivatives stimulates the release of epinephrine and norepinephrine from the sympathoadrenal system in man,7' 8 the extent to which this response may be dose-or concentration-dependent has only been studied in an in vitro system, the isolated perfused adrenal gland.9' 10 Epinephrine and norepinephrine are known to have chronotropic and inotropic effects on the heart, which, together with vasoconstrictor effects, lead to an increase

1 Ageing is associated with a decline in ,3-adrenergic responsiveness in several tissues.Reduced ,-adrenoceptor mediated smooth muscle relaxation in aged man has been demonstrated using the dorsal hand vein technique. Isoprenaline and adenosine activate adenylate cyclase through separate membrane bound receptors to induce vasodilatation.2 To determine the specificity of reduced ,-adrenergic responsivenes.s in smooth muscle of aged man, and possible sites of the defect responsible, venodilatory responses to isoprenaline, a ,B-adrenoceptor agonist and adenosine were determined in nine young (age 26 ± 3 years: mean ± s.d.) and eight elderly (age 70 ± 5 years), healthy male volunteers. Veins were partially constricted with the axl-adrenoceptor agonist phenylephrine and increasing doses of adenosine (5 to 1220 ,ug min-') or isoprenaline (271 ng min-1) were infused. 3 Maximal dilatation induced by isoprenaline was 83 ± 26% in the young and 51 ± 34% in the elderly, P = 0.02. Maximal dilatation induced at th-highest dose of adenosine (1220 jig min-') was similar in young and elderly: 79 ± 25% vs 88 ± 28%, P = 0.26.4 Adenosine venodilatation was measured before and after infusions of theophylline (6.8 to 135 ,ug min-') for 30 min in six subjects. Adenosine responsiveness was unchanged following theophylline: 48 ± 16% to 49 ± 40%, P = 0.44. 5 The results suggest that the age-associated reduced responsiveness of the ,3-adrenergic system in human vascular smooth muscle is not shared by venodilatation mediated by adenosine.