tolerance and subjective fatigue after metoprolol and atenolol in

Transcription

1 Br. J. clin. Pharmac. (1991), 31, ADONIS C Influence of debrisoquine oxidation phenotype on exercise tolerance and subjective fatigue after metoprolol and atenolol in healthy subjects R. V. LEWIS, L. E. RAMSAY, P. R. JACKSON, W. W. YEO, M. S. LENNARD & G. T. TUCKER University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Glossop Road, Sheffield S1 2JF 1 The effects of single doses of metoprolol 5 mg, metoprolol 1 mg and atenolol 1 mg on exercise tolerance were compared with placebo in a double-blind random crossover study in 12 healthy subjects. Nine subjects were extensive metabolisers of debrisoquine, and three were poor metabolisers. 2 Three hours after dosing 13-adrenoceptor blocker treatments significantly reduced exercise heart rate, prolonged time to complete exercise, and increased subjective fatigue measured by visual analogue scale. 3 Scores for subjective fatigue did not correlate with reduction in exercise heart rate or prolongation of exercise time. Exercise time prolongation was weakly but not significantly correlated with exercise heart rate reduction. 4 When compared with placebo, prolongation of exercise time and increased fatigue with metoprolol were not significantly related to debrisoquine oxidation phenotype or to the debrisoquine/4-hydroxydebrisoquine (D/4H-D) ratio. 5 When metoprolol responses were compared with those for atenolol, changes in exercise time and fatigue scores were significantly related to oxidation phenotype. For metoprolol 1 mg, poor metabolisers required 2.8 s longer to complete exercise (P <.5) and had higher fatigue scores by 78% (P <.5) as compared with extensive metabolisers. Changes in exercise time for metoprolol 1 mg, when compared with atenolol, correlated highly with the D/4H-D ratio in all subjects (r =.81, P <.2) and within extensive metabolisers (r =.7, P <.5, n = 9). 6 Exercise time and fatigue responses to metoprolol, as compared with placebo, were predicted much more strongly by the corresponding responses to atenolol than by the D/4H-D ratio. 7 These data suggest that subjective fatigue with,-adrenoceptor blocker treatment is unrelated to,3-adrenoceptor blockade as conventionally measured. Fatigue with metoprolol is determined mainly by pharmacodynamic factors with relatively little contribution from genetic variation in metabolism. In the clinical setting genetic polymorphism may have little discernible influence on side-effects of metoprolol in cross-sectional studies. It may nevertheless have some implication for the choice or dose of,b-adrenoceptor blocker in individual subjects. Keywords metoprolol atenolol debrisoquine oxidation phenotype Introduction The metabolism of the P-adrenoceptor blocking drug debrisoquine have higher peak plasma drug concentrametoprolol is strongly influenced by the oxidation pheno- tions, prolonged terminal elimination half-lives, and type determined using debrisoquine (Lennard et al., sixfold higher area under the plasma concentration-time 1982; McGourty et al., 1985). Poor metabolisers of curve of metoprolol when compared with extensive Correspondence: Dr L. E. Ramsay, University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Glossop Road, Sheffield S1 2JF 391

2 392 R. V. Lewis et al. metabolisers (Lennard et al., 1982). Extensive metabolisers have a significantly shorter duration of,b-adrenoceptor blockade (Lennard et al., 1982; McGourty et al., 1985) even with some sustained release formulations of metoprolol (Freestone et al., 1982; Silas et al., 1985). This may have implications for the clinical use of metoprolol, as extensive metabolisers may have inadequate antianginal (Ledermann et al., 1985; Lennard et al., 1982) and antihypertensive effects (Silas et al., 1985) at the end of a dose interval. Suggestions that the oxidation phenotype may influence the incidence of adverse reactions to metoprolol (Alvan et al., 1982; Lennard et al., 1982), have prompted considerable debate (Jack & Wilkins, 1984; Lennard et al., 1984; Idle & Smith, 1984; Regardh & Johnsson, 1984). Alvan et al. (1982) proposed that poor metabolisers may be at risk of side-effects related to unusually high plasma concentrations of metoprolol if they are treated with the drug at conventional dosage. Jack & Wilkins (1984) thought this unlikely, pointing out that even extreme variability of plasma concentrations is unimportant for drugs which, like metoprolol, have a wide therapeutic ratio. The limited clinical data available tend to support the latter view. Although Wagner et al. (1987) implicated the poor metaboliser state in one severe interaction between metoprolol and diltiazem, formal studies have failed to show any relation between the oxidation phenotype and adverse effects of metoprolol (Clark et al., 1984; Clark & Edwards, 1988). However the possible influence of genetic polymorphism of metoprolol metabolism on subtle side-effects of the drug, such as tired legs and cold extremities (Lewis et al., 1984; Lewis et al., 1985a), has not been examined (Lennard et al., 1984).,-adrenoceptor blockers undoubtedly do have a wide therapeutic ratio, as Jack & Wilkins (1984) suggest, and any adverse effects related to the high plasma metoprolol concentrations in poor metabolisers are unlikely to be a direct consequence of excess,-adrenoceptor blockade. One possible exception to this might be a loss of p1-selectivity with high plasma concentrations of metoprolol (Lennard et al., 1982). Setting this aside, the point at issue is whether,-adrenoceptor blockers cause predictable side-effects which are independent of,-adrenoceptor blockade, as conventionally measured. If so, are such side-effects with metoprolol related to genetic polymorphism of its metabolism? Any influence of the oxidation phenotype will depend upon the relative contribution of pharmacokinetic and pharmacodynamic factors to the variation between subjects in these sideeffects of metoprolol. If pharmacodynamic variability is far larger than that related to pharmacokinetics, the genetic influence on metabolism would have little discernible effect on between-subject variability. If on the other hand pharmacokinetic differences contribute more than pharmacodynamics to between-subject variability, the oxidation phenotype may influence subjective sideeffects with metoprolol. We have explored the contribution of oxidation phenotype and pharmacodynamic factors to impaired exercise tolerance and subjective fatigue in healthy subjects treated with single doses of metoprolol. Single doses of,-adrenoceptor blockers impair endurance and increase perceived exertion in healthy subjects (Pearson et al., 1979), and fatigue is a side-effect which can be quantified consistently in patients taking P-adrenoceptor blockers (Lewis et al., 1984; Lewis et al., 1985a). The mechanism of fatigue with,-adrenoceptor blockade is poorly understood, but it appears to relate poorly if at all to the haemodynamic effects of,-adrenoceptor blockade (Hall et al., 1984). The objective and subjective effects of metoprolol on exercise were compared with those of placebo and another P-adrenoceptor blocker, atenolol. Atenolol was included for comparison because it is cleared largely by the kidney, its disposition is not related to the debrisoquine oxidation phenotype (Lewis et al., 1985b), and plasma atenolol concentrations after a given dose vary litttle between healthy subjects (Ledermann et al., 1985; Lewis et al., 1985b). Any variability in response to atenolol is therefore likely to be determined largely by pharmacodynamic factors, with little contribution from pharmacokinetic differences. We have examined what proportion of the variation in objective and subjective fatigue with metoprolol could be predicted by the debrisoquine metabolic ratio, a measure of genetically-influenced kinetic variability, and what proportion by the response to atenolol, a measure of pharmacodynamic variability. Methods Subjects Twelve healthy subjects (seven men, five women; mean age 28 years) gave written informed consent to the study which was approved by the hospital ethics committee. Nine of the 12 were known to be extensive metabolisers, and three poor metabolisers, of debrisoquine by prior phenotyping using the ratio debrisoquine to 4-hydroxydebrisoquine (D/4H-D) in overnight urine following a single 1 mg dose of the drug (Lennard et al., 1977). Study design At a preliminary visit the exercise test which was used throughout the study for each individual was determined, as described below. The subjects then entered a fourphase random crossover trial comparing single doses of four treatments, with the four study phases being separated by intervals of at least 1 week. The four treatments were: - metoprolol tartrate 5 mg - metoprolol tartrate 1 mg - atenolol 1 mg - placebo Tablets were enclosed in gelatin capsules to render the study double-blind, and were taken with 1 ml water 3 h prior to the exercise test. One week after completion of the four randomised test phases subjects performed a further exercise test without treatment to determine whether any training effect had occurred during the study. Exercise testing At the preliminary visit subjects stepped on and off a 4 cm high step as rapidly as possible until heart rate

3 Oxidation phenotype: metoprolol and atenolol 393 increased to 9% of the predicted maximum for age and sex, or until exhaustion. The number of steps required was used as the standard test for the individual throughout the study. At the end of each exercise test the time taken to complete the standard exercise was recorded, subjective fatigue was assessed by marking a 1 cm visual analogue scale, and heart rate was measured by ECG. All exercise tests were performed at the same time of day to avoid diurnal changes in exercise performance. Exercise tests during the randomised phases of the study commenced exactly 3 h after trial treatments were given, a time expected to correspond to peak plasma concentrations of metoprolol and atenolol (Lennard et al., 1982; Lewis et al., 1985b). At this time plasma metoprolol concentrations are threefold higher in poor metabolisers than extensive metabolisers (Lennard et al., 1982; McGourty et al., 1985). Statistical analysis Comparison of the pre-study, randomised placebo, and post-study exercise tests showed no evidence of a training effect over the period of study. To examine for order effect parametric analysis of variance was performed on log transformed exercise times, raw heart rates, and visual analogue scores transformed to normal distribution. These analyses showed no significant order effects. Further statistical analysis was by Friedman's analysis of variance, followed where significant differences were found by the Wilcoxon signed ranks test to compare between pairs of treatments. Comparison of differences between extensive and poor metabolisers was by the Mann-Whitney U test. The relations of the debrisoquine/ 4-hydroxydebrisoquine (D/4H-D) ratio and atenolol response to metoprolol responses were examined by Pearson's correlation coefficient and forward stepwise multiple regression using SPSS/PC+ (version 3., SPSS Inc. 1988). The inverse of D/4H-D ratio (D/4H-D inverse) was used for analysis as this metameter better displays differences within the group of extensive metabolisers. Two-tailed tests of significance were used throughout, but values of P <.1 are cited for comparisons where a strong prior hypothesis existed. Results Comparison of treatments (Table 1) The post-exercise heart rate differed highly significantly (P <.1) among the four treatments, with metoprolol 5 mg, metoprolol 1 mg, and atenolol 1 mg all reducing heart rate from placebo values (all P <.1). Values for metoprolol 1 mg and atenolol 1 mg were significantly lower than those for metoprolol 5 mg (both P <.1). The time taken to complete the exercise test (exercise time) differed significantly between treatments (P <.5) with the exercise time on atenolol 1 mg prolonged when compared with placebo (P <.5) and with metoprolol 1 mg (P <.5). Perception of fatigue measured by visual analogue scale (fatigue score) differed significantly between the four treatments (P <.1), with fatigue scores higher for metoprolol 5 mg (P <.5), metoprolol 1 mg (P <.1), and atenolol 1 mg (P <.2) than for placebo. Fatigue scores for the three,b-adrenoceptor blocker treatments did not differ significantly on direct comparison. Relations of exercise time and fatigue to P-adrenoceptor blockade As can be seen from Table 1 changes in subjective fatigue scores with,-adrenoceptor blockers were more pronounced than were changes in objective exercise time. The relations of increase in exercise time and increase in fatigue score to reduction in exercise heart rate, the conventional measure of,b-adrenoceptor blockade, were examined for all three P-adrenoceptor blocker treatments (Table 2). There were weak but nonsignificant positive correlations between reduction in exercise heart rate and increase in exercise time. However subjective fatigue as measured by the visual analogue scale showed no consistent relationship to reduction in heart rate, or to increase in exercise time. Responses to atenolol Comparison of atenolol and placebo showed wide variation between individual subjects in responses to atenolol. Table 1 Mean (and s.d.) results of exercise test in 12 healthy subjects Placebo MetoprololSmg MetoprolollOOmg AtenolollOOmg Heart rate ***a 123.1*** 114.3*** (beats min-') (13.6) (15.2) (18.6) (23.1) Exercise time * (s) (64) (69) (73) (77) Fatigue score * 62.4*** 67.7** (mm) (26.1) (28.1) (28.4) (26.6) *P <.5; **P <.2; ***P <.1 vs placebo. ap <.1 vs metoprolol 1 mg and atenolol 1 mg. bp <.5 vs metoprolol 1 mg.

4 394 R. V. Lewis et al. Table 2 Simple correlations between fall in heart rate, increase in exercise time, and increase in fatigue score from placebo values, for the three,b-adrenoceptor blocker treatments Heart rate Heart rate Exercise time vs vs vs exercise time fatigue score fatigue score Metoprolol 5 mg Metoprolol 1 mg Atenolol 1 mg For change in exercise time the range in individuals was from a reduction of 4% to an increase of 19%. Betweensubject variation was even more marked for fatigue score, with the score of atenolol falling by 36% in one subject and increasing by 14% at the other extreme. Metoprolol vs placebo: role of oxidation phenotype (Table 3) When compared with extensive metabolisers (n = 9), the three poor metabolisers of debrisoquine had lower heart rate and increased fatigue score on metoprolol 5 mg, and lower heart rate, increased exercise time and increased fatigue score with metoprolol 1 mg. However none of these differences reached statistical significance. Correlations of the D/4H-D (inverse) ratio with responses to metoprolol (when compared with placebo) are shown in Table 4a. These correlations were generally negative, indicating prolonged exercise time and higher fatigue score with higher D/4H-D ratios, i.e. in poor metabolisers, but they were weak and did not reach significance. Metoprolol vs atenolol: role of oxidation phenotype (Table 5) When compared with the results for atenolol 1 mg, poor metabolisers of debrisoquine had prolonged exercise time and increased fatigue scores, while extensive metabolisers had shortened exercise time and reduced fatigue scores, after treatment with metoprolol 1 mg. The difference between poor and extensive metabolisers was significant for exercise time (P <.5, Figure 1) and approached significance for fatigue score -W. x 2 r w L Figure 1 Difference between metoprolol 1 mg and atenolol 1 mg in time taken to complete exercise test. Negative values indicate a shorter time after metoprolol 1 mg. Results for nine EM (hatched bars) and three PM (solid bars). Table 3 Mean responses to,b-adrenoceptor blocker treatments compared with placebo values in extensive metabolisers (EM; n = 9) and poor metabolisers (PM; n = 3) of debrisoquine Metoprolol5 mg Metoprolol 1mg Atenolol 1 mg EM PM EM PM EM PM Change in heart rate (beats min-s) Change in exercise time (s) Change in fatigue score (mm) Table 4 Correlations of D/4H-D (inverse) against a) metoprolol responses when compared with placebo, and b) metoprolol response when compared with atenolol 1 mg (a) vs placebo (b) vs atenolol MetSOmg MetlOOmg Met5Omg MetlOOmg Change in exercise time (s) **t % change in exercise time **t Change in fatigue score (mm) % change in fatigue score * * *P <.1; **P <.2. t for EM alone, r = -.7, P <.5, n = 9; t for EM alone, r = -.67, P <.5, n = 9.

5 Oxidation phenotype: metoprolol and atenolol 395 Table 5 Mean responses to metoprolol when compared with those for atenolol 1 mg in EM (n = 9) and PM (n = 3) A heart rate A exercise time (s) A % exercise time A fatigue score (mm) A % fatigue score MetoprololSO mg Metoprolol 1 mg EM PM EM PM ** *** * * ** *P <.1; **P <.5; ***P <.2 for differences between PMs and EMs. (P <.1, Figure 2a). These differences were present also when these variables were expressed as percentage changes (poor metabolisers vs extensive metabolisers: percent exercise time P <.2; percent fatigue score P <.5, Figure 2b). These differences between poor and extensive metabolisers were substantial. After metoprolol 1 mg extensive metabolisers completed the exercise test significantly more quickly th-an they did after atenolol 1 mg, by a mean of 14.1 ± s.d s (P <.1). In contrast poor metabolisers completed the exercise test more slowly, by a mean of 6.7 ± s.d. 11. s. Extensive metabolisers had lower fatigue scores by 17% after metoprolol 1 mg when compared with atenolol 1 mg, whereas poor metabolisers had fatigue scores 61% higher with metoprolol 1 mg..2 E 1 E a Y-.... l 3-2- <1 E Figure 3 Difference between metoprolol 5 mg and atenolol 1 mg in fatigue scores after exercise. Negative values indicate less fatigue after metoprolol 5 mg. Results for nine EM (hatched bars) and three PM (solid bars). After metoprolol 5 mg poor metabolisers of debrisoquine had higher fatigue scores, and extensive metabolisers lower fatigue scores, when compared with atenolol 1 mg. This difference between poor and extensive metabolisers (Table 5; Figure 3) approached significance (P <.1). There was a non-significant trend for poor metabolisers to have prolonged exercise time and extensive metabolisers shorter exercise time after metoprolol 5 mg, when compared with atenolol 1 mg (Table 5). Metoprolol response relative to atenolol, and the D14H-D ratio The responses to metoprolol 5 mg and metoprolol 1 mg relative to those for atenolol 1 mg were calculated by subtracting the values for atenolol 1 mg in each individual. Correlations between these adjusted responses to metoprolol and the D/4H-D (inverse) ratio were examined (Table 4b). There were highly significant relations between the D/4H-D ratio and the changes in exercise time from atenolol values with metoprolol 1 mg (Table 4b, Figure 4). It is of note that this correlation was also statistically significant (P <.5) I... ) L., b n E a) 4._._ ) x ) 2 r 1. -1_ -2 _ a a U All subjects r = -.81, P <.2 EMs r = -.7, P <.5 '1-1 L.' Figure 2 Difference between metoprolol 1 mg and atenolol 1 mg in fatigue scores after exercise, expressed as a) absolute and b) % change. Negative values indicate less fatigue after metoprolol 1 mg. Results for nine EM (hatched bars) and three PM (solid bars). -3 L L Ratio D/4H-D (inverse) Figure 4 Difference in exercise time between metoprolol 1 mg and atenolol 1 mg in 12 subjects related to D/4H-D ratio expressed as inverse to show relation in extensive metabolisers. Negative values indicate a shorter time after metoprolol 1 mg. = PM; O = EM. 4

6 396 R. V. Lewis et al. ) Ln.) U) Co - 15r * 1 5so -5H I r =-.55, P <.1 3 o prediction in the multiple regression, but again the response to atenolol was a better predictor of responses to metoprolol 5 mg than was the D/4H-D ratio (Table 6). Discussion P-adrenoceptor blockade, exercise tolerance and fatigue -1 L The simple exercise test used proved sensitive enough LI to separate the,3-adrenoceptor blocker treatments from placebo as regards reduction in exercise heart rate, time Ratio D/4IH-D (inverse) to complete the exercise, and subjective fatigue measured Figure 5 Difference in fatigue score between metoprolol 1 by visual analogue scale. Three hours after treatment, mg and atenolol 1 mg, expressed as; % change, related to which approximates to the time of peak plasma concentra- D/4H-D ratio expressed as inverse.: Negative values indicate tions after metoprolol and atenolol (Lennard et al., less fatigue after metoprolol 1 mg. * = PM; a = EM. 1982; Lewis et al., 1985b), there was no significant difference in the degree of,b-adrenoceptor blockade achieved with metoprolol 1 mg and atenolol 1 mg, within the group of extensive metabolisers (n = 9), as shown by reductions in exercise heart rate, but there indicating that it was not a cotnsequence of arbitrary was a non-significant trend to increased,-adrenoceptor selection for study of subject;, s who were poor and blockade with atenolol 1 mg. Prolongation of time to extensive metabolisers. There wras a similar but weaker complete exercise after,3-adrenoceptor blocker treatcorrelation between the D/41H-D ratio and change ments showed only weak and non-significant correlations in fatigue score after metoprolol 1 mg (Table 4b, to reduction in exercise heart rate. Furthermore, subjective fatigue showed no relation to reduction in exercise Figure 5). heart rate or the time taken to complete exercise, although Metoprolol responses predicted from atenolol response the fatigue scores differed markedly from placebo values. and D14H-D ratio The sensation of subjective fatigue, which is a common and important side-effect of 3-adrenoceptor blockers The relations of atenolol response and D/4H-D (inverse) in clinical practice (Lewis et al., 1984, 1985a), appears to the effects of metoprolol, when compared with placebo, to be unrelated to the degree of 13-adrenoceptor were examined by simple correlations and multiple blockade. This observation is in agreement with the regression analysis (Table 6). These two variables conclusions of Hall et al. (1984), who have reviewed the accounted for 78% of the variance in exercise time relation of fatigue to,-adrenoceptor blocker treatment. response (P <.5), and 67% if the variance in fatigue score (P <.2), after metoprrolol 1 mg. The cor- Response to atenolol responding simple correlations (Table 6) showed that these effects of metoprolol 1 nag were predicted much Individual subjects varied markedly in their responses more strongly by the responses to atenolol than by the to atenolol, a P-adrenoceptor blocker which shows D/4H-D ratio. The D/4H-D iratio explained only 8% relatively little variability in pharmacokinetics between (r2) of the variance in exercise tirne and 18% of variance healthy subjects (Ledermann et al., 1985; Lewis et al., in fatigue score in response to nnetoprolol 1 mg. The 1985b). The change in time to complete exercise varied corresponding responses to ateriolol explained a much from -4% to +19% when compared with placebo, and larger proportion of the total variance (Table 6). A the change in fatigue score showed even larger variation similar analysis, for metoprolol 5 mg showed weaker between subjects, from -36% to +14%. Although Table 6 Contribution of atenolol response and D/4H-D (inverse) to the responses to metoprolol, when compared with placebo, assessed by simple correlation and multiple regression analysis Metoprolol 5 mg Metoprolol 1 mg AT D/4H-D r2 AT D/4H-D r2 Change in exercise time (s).68**.6.51*.67** t % change in exercise time ** Change in fatigue score (mm) t ** % change in fatigue score *P <.5; **P <.2; tp <.1; tp <.5.

7 Oxidation phenotype: metoprolol and atenolol 397 plasma concentrations of atenolol were not measured in the present study, it is clear from previous studies that these wide differences in response are unlikely to be caused by between-subject differences in plasma atenolol concentration (Ledermann et al., 1985; Lewis et al., 1985b). We conclude that the considerable variation between subjects in objective and subjective fatigue after atenolol is probably related to pharmacodynamic factors. Responses to metoprolol Metoprolol shows genetic polymorphism in its metabolism such that poor and extensive metabolisers have very large differences in plasma concentrations of metoprolol (Lennard et at., 1982; McGourty et al., 1985). Previous studies have shown that genetic polymorphism influences the duration of 13-adrenoceptor blockade after metoprolol (Freestone et al., 1982; Lennard et al., 1982; McGourty et al., 1985; Silas et al., 1985). The question posed in this study was whether genetic polymorphism of metoprolol metabolism would have a discernible effect on two side-effects of metoprolol, the increase in time taken to complete a strenuous exercise test, and subjective fatigue during strenuous exercise. A second question was what impact genetic polymorphism would have when compared with the influence of pharmacodynamics on these effects of,-adrenoceptor blocker treatment. The responses to atenolol were taken as a measure of the importance of pharmacodynamics on these effects. At the time of testing, 3 h after dosing, poor metabolisers have plasma metoprolol concentrations threefold higher than those of extensive metabolisers (Lennard et al., 1982; McGourty et al., 1985). Genetic polymorphism had no clear or significant effect on the responses to metoprolol when they were compared with placebo treatment. When examined in this way metoprolol responses did not differ between poor and extensive metabolisers, and the effects of metoprolol did not correlate significantly with the D/4H-D ratio. However there was a clear relationship of genetic polymorphism to exercise time and fatigue scores when these responses to metoprolol were compared with, or 'corrected' for, those to atenolol. This was shown by comparing extensive and poor metabolisers (Table 5) and by correlations of the D/4H-D ratio with changes in exercise time and fatigue scores (Figures 1,2 and 3). It is of note that the correlation for exercise time was present and significant within the extensive metabolisers (Figure 4), indicating that the overall correlation was not a consequence of the selection of the subjects from two phenotypic groups. It is important to understand exactly what these relations mean. When the responses to metoprolol are compared with, or 'corrected' for, those to atenolol, any pharmacodynamic contribution to variability in responses is effectively stripped out, unmasking any influence of genetic polymorphism. When one source of variability is removed in this way, the influence of a second source of variability, in this case genetic polymorphism, may be greatly exaggerated. These analyses indicate only that genetic polymorphism has some effect on exercise time and fatigue after metoprolol, but they do not quantitate its contribution to the total variability observed. To quantitate the relative importance of genetic polymorphism and pharmacodynamic factors in determining exercise time and fatigue after metoprolol, we examined the proportion of variance which could be explained by the responses to atenolol (representing pharmacodynamic variability) and by the D/4H-D ratio (the measure of genetic polymorphism). For metoprolol 1 mg a major part of the variance in exercise time and fatigue score responses could be explained in terms of these two variables (Table 6), indicating that the experimental conditions were satisfactory for our purpose. It is evident from Table 6 that these effects of metoprolol 1 mg were predicted much more powerfully by responses to atenolol 1 mg than by the D/4H-D ratio. The implication is that pharmacodynamic factors were much more important than genetic polymorphism in explaining between-subject variability in impaired exercise tolerance and subjective fatigue after metoprolol. In summary, subjective fatigue appears to be unrelated, and exercise tolerance only weakly related, to,-adrenoceptor blockade as conventionally measured. After metoprolol these adverse effects are related to the oxidation phenotype, but only after 'correcting' for the effects of atenolol. The contribution of the oxidation phenotype to fatigue and impaired exercise tolerance appears to be overwhelmed by the contribution of pharmacodynamic factors to these adverse effects. Possible implications What implications may these findings have for the use of metoprolol in ordinary practice? One must be cautious in extrapolating findings from a study of single doses of metoprolol in healthy subjects performing near-maximal exercise to chronic use of the drug in patients who may never exercise to this degree. Nevertheless some tentative conclusions may be drawn. Perhaps the most important is that the influence of genetic polymorphism in metoprolol metabolism may be very different when one considers the situation between patients and within patients. The between-patient situation would be exemplified by considering a population of patients, with hypertension for example, treated with a fixed dose of metoprolol. In these patients the occurrence of subjective side-effects such as fatigue or tired legs may well be determined largely by pharmacodynamic factors, with relatively little effect of pharmacokinetic differences related to the genetic polymorphism in metabolism. The results of the present study suggest that any effect of the oxidation phenotype or D/4H-D ratio on side-effects is likely to be obscured by pharmacodynamic differences. This is consistent with the evidence from clinical studies (Clark et al., 1984; Clark & Edwards, 1988). However the conclusions may be different when considering the situation within patients. This is illustrated best by examining the effect of the two,-adrenoceptor blockers studied here on individual subjects. In the whole group metoprolol 1 mg was slightly but not significantly less potent than atenolol 1 mg, as judged by the reduction in exercise heart rate, and subjects completed the strenuous exercise significantly more quickly after metoprolol 1 mg. However these mean data conceal important and significant differences

8 398 R. V. Lewis et al. between poor and extensive metabolisers. When compared with atenolol treatment poor metabolisers had impaired exercise tolerance and increased fatigue with metoprolol 1 mg. Indeed the poor metabolisers had an increase in these subjective effects even with 5 mg of metoprolol (Figure 3, Table 5). We can only speculate on the outcome had the two,b-adrenoceptor blockers been compared at the doses now used routinely in the treatment of hypertension, which are 2 mg daily for metoprolol and 5 mg daily for atenolol. The caveat concerning extrapolation from this acute study to longterm clinical use must be repeated, but it is certainly possible that the 9% of patients who are poor metabolisers may be disadvantaged if they are treated routinely with metoprolol at a dose of 2 mg daily. The fact that genetic polymorphism is likely to contribute only a small part to the total burden of side-effects experienced by a population of patients treated with P-adrenoceptor blockers would be little consolation to those affected. There is a need for studies comparing the effects of longterm treatment with metoprolol with those of P-adrenoceptor blockers which are free of genetically influenced variability in metabolism, looking specifically at the effect of the oxidation phenotype on subtle unwanted effects such as fatigue. References Alvan, G., von Barr, C., Seideman, P. & Sjoqvist, F. (1982). High plasma concentrations of 3-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet, i, 333. Clark, D. W. J. & Edwards, I. R. (1988). Adverse drug reaction reporting and retrospective phenotyping for oxidation polymorphism. Med. Toxicol., 3, Clark, D. W. J., Morgan, A. K. W. & Waal-Manning, H. (1984). Adverse effects from metoprolol are not generally associated with oxidation status. Br. J. clin. Pharmac., 18, Freestone, S., Silas, J. H., Lennard, M. S. & Ramsay, L. E. (1982). Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing. Br. J. clin. Pharmac., 14, Hall, P. E., Kendall, M. J. & Smith, S. R. (1984). Beta blockers and fatigue. J. clin. hosp. Pharm., 9, Idle, J. R. & Smith, R. L. (1984). Protecting the poor metaboliser-from Jack & Wilkins. Br. J. clin. Pharmac., 17, Jack, D. B. & Wilkins, M. R. (1984). Protecting the poor metaboliser-from what? Br. J. clin. Pharmac., 17, Ledermann, H., Bippi, H., Boekens, H., Frolich, J. H., Herrmann, H. & Schmitt-Landherr, K. (1985). Variability in the pharmacokinetics of atenolol and metoprolol. Arzneim-Forsch. Drug. Res., 35, Lennard, M. S., Jackson, P. R., Ramsay, L. E., Tucker, G. T. & Woods, H. F. (1984). Protecting the poor metaboliser-from Jack & Wilkins. Br. J. clin. Pharmac., 17, Lennard, M. S., Silas, J. H., Freestone, S., Ramsay, L. E., Tucker, G. T. & Woods, H. F. (1982). Oxidation phenotype -a major determinant of metoprolol metabolism and response. New Engl. J. Med., 37, Lennard, M. S., Silas, J. H., Smith, A. J. & Tucker, G. T. (1977). Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J. Chromatogr., 133, Lewis, R. V., Jackson, P. R. & Ramsay, L. E. (1984). Quantification of side-effects of P-adrenoceptor blockers using visual analogue scales. Br. J. clin. Pharmac., 18, Lewis, R. V., Jackson, P. R. & Ramsay, L. E. (1985a). Sideeffects of 13-adrenoceptor blockers assessed by visual analogue scales. Br. J. clin. Pharmac., 19, Lewis, R. V., Lennard, M. S., Jackson, P. R., Tucker, G. T., Ramsay, L. E. & Woods, H. F. (1985b). Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br. J. clin. Pharmac., 19, McGourty, J. C., Silas, J. H., Lennard, M. S., Tucker, G. T. & Woods, H. F. (1985). Metoprolol metabolism and debrisoquine oxidation polymorphism-population and family studies. Br. J. clin. Pharmac., 2, Pearson, S. B., Banks, D. C. & Patrick, J. M. (1979). The effect of 13-adrenoceptor blockade on factors affecting exercise tolerance in normal man. Br. J. clin. Pharmac., 8, Regardh, C. G. & Johnsson, G. (1984). Interindividual variations in metoprolol metabolism - some clinical and other observations. Br. J. clin. Pharmac., 17, Silas, J. H., Freestone, S., Lennard, M. S. & Ramsay, L. E. (1985). Comparison of two slow-release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients. Br. J. clin. Pharmac., 2, Wagner, F., Jahnchen, E., Trenk, D., Eichelbaum, M., Harmasch, P., Hauf, G. & Roskamm, H. (1987). Severe complications of antianginal drug therapy in patients identified as poor metabolizers of metoprolol, propafenone, diltiazem, and sparteine. Klin. Wochenschr., 65, (Received 12 September 199, accepted 28 November 199)