DRUG EXPERIENCE

Drug Safety 7 (I): 54-70, 1992 0114-5916/92/000 1-0054/$08.50/0 © Adis International Limited. All rights reserved. ORSI51.

Risks Versus Benefits of Inhaled ,B2-Agonists in the Management of Asthma Brian J. Lipworth Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, Scotland

Contents 54 55 55

56 56

57 58 58 59 61 62 62

63 64 64

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Summary

Summary I. Pharmacology of !'l2-Agonists 1.1 Molecular Structure of !'l2-Agonists 1.2 Site and Action of !'l2-Adrenoceptors 1.3 In Vitro Selectivity of !'l2-Agonists 2. Bronchodilator Effects 3. Systemic Effects 3.1 Hypokalaemic and Electrocardiographic Effects 3.2 Chronotropic and Inotropic Effects 3.3 Comparative Systemic Effects of !'l2-Agonists 4. Tachyphylaxis 4.1 In Vivo Studies 4.2 In Vitro Studies 4.3 Corticosteriod Effects 5. Disease Control 6. Novel !'l2-Agonists 7. Conclusions

The therapeutic goal for the treatment of asthma should be to suppress bronchial mucosal inflammation with preventive drugs such as inhaled corticosteroids, and to relieve symptoms of wheezing and breathlessness with bronchodilator drugs. The lower recommended doses of inhaled !'lz-agonists produce rapid effective bronchodilatation without systemic adverse effects; higher doses may produce substantial improvements in airway response which may help patients with more severe airflow obstruction. Higher doses of inhaled Ih-agonists also cause dose-related systemic adverse !'lz effects including tremor, tachycardia, hypokalaemia and associated electrocardiographic sequelae. In this respect, although fenoterol appears to cause greater extrapulmonary !'lz-mediated adverse effects at higher doses, there is no evidence to suggest that it is any less !'lzselective. There is also some evidence to suggest that use of regular inhaled Ih-agonists may cause increased bronchial hyperreactivity and possibly deterioration in disease control. Patients who require such regular use should therefore be given additional anti-inflammatory therapy with inhaled corticosteroids. The recent availability of novel, longer-acting inhaled !'l2-agonists such as salmeterol and formoterol will also make necessary a careful reappraisal of their long term use in patients with asthma.

55

Risks and Benefits of P2-Agonists

The therapeutic goal for patients with asthma should be to suppress bronchial mucosal inflammation with preventive-type drugs such as inhaled corticosteroids, and to relieve symptoms ofwheezing and breathlessness with bronchodilator therapy. Inhaled {j2-agonists have been used for more than 30 years and remain as first-line bronchodilator therapy for most asthmatic patients. Initial concerns regarding their safety were raised in the 1960s in England and Wales; the transient rise in mortality during this period was thought to be associated with an increased use of isoprenaline (isoproterenol) aerosol sprays (Inman & Adelstein 1969; Speizer et al. 1968). Isoprenaline resistance was suggested as a possible explanation, although this was never proven (Paterson et al. 1968; Reisman 1970). A second wave of asthma mortality occurred in New Zealand in the late 1970s (Jackson et al. 1982), and was attributed by some authors to the introduction of fenoterol. Case-control studies suggested an association between the use of inhaled fenoterol and an increased risk of death in severe asthma (Crane et al. 1989a; Grainger et al. 1991; Pearce et al. 1990). Studies showing that the extrapulmonary effects of fenoterol are greater in comparison with other inhaled {j2-agonists have led to speculation that its systemic adverse effects might explain the epidemiological mortality data (Crane et al. 1989b; Windom et al. 1990; Wong et al. 1990). This was compounded by a recent report from New Zealand (Sears et al. 1990) suggesting that regular inhaled {j2-agonist therapy might cause worsening control in patients with asthma. These data, along with the recent introduction of novel, longer-acting inhaled {j2-agonists, have stimulated renewed interest in the risk-benefit equation of these agents, and have provided the stimulus for this review.

1. Pharmacology

0/ {j2-Agonists

It is first important to become familiar with some of the basic pharmacology of {j2-agonists and {j2-adrenoceptors, in order to fully understand the factors which determine the efficacy, systemic ef-

Basic nucleus

\ 01

Catecholamines

OH I OH

-

\

°IH ~ ,-CH(CH3)2 -C-N I I 'H H H

Isoprenaline (isoproterenol)

V" C-C-N)CH2)6-0-(CH2)4-o~

HO I

OH H

\

CH20H

~ ~

'H

Salmeterol

Fig. 1. The molecular structure of fj-adrenoceptor agonists.

fects and selectivity of inhaled {j2-agonists which occur in vivo. 1.1 Molecular Structure of {j2-Agonists The {j-adrenoceptor agonists can be broadly divided into the catecholamines and noncatecholamines. The former includes the synthetic compound isoprenaline, and the latter compounds such as salbutamol (albuterol), terbutaline and fenoterol (fig. I). The noncatecholamines differ in their N-substitutions in the basic phenylethanolamine nucleus, as well as substitutions of hydroxyl groups in the benzene ring. These modifications confer resistance to breakdown by catechol-O-methyltransferase (COMT) and reduce their efficacy for {jl-receptors, making them relatively more {j2-selective compared with isoprenaline. The novel longer-

Drug Safety 7 (1) 1992

56

acting Ih-agonist salmeterol differs in possessing a much longer substitution in the amine head. It is thought that its molecular configuration might result in exoreceptor binding with prolonged receptor occupancy, and hence a long duration of action (Jack 1991). It is interesting that formoterol, which is also long acting, does not possess a long amine side-chain, making exoreceptor binding unlikely with this compound. However, both salmeterol and formoterol are highly lipophilic molecules, which may result in greater tissue retention and could also account for their duration of action (Jeppsson et al. 1989). This same property oflipophilicity might also conceivably result in increased systemic absorption across the lung-vascular bed, and hence lead to greater systemic effects. 1.2 Site and Action of ~2-Adrenoceptors Lands et al. (1967) classified ~-adrenoceptors into ~1 and ~2 subtypes on the basis of their respective affinity for noradrenaline and adrenaline. Receptors of the ~ 1 subtype are mainly located in the heart, whereas ~2-receptors are more widespread (table I). It is now known that up to 50% of atrial and ventricular ~-receptors are of the ~2subtype (Bristow & Ginsburg 1986; Brodde et al. 1983; Heitz et al. 1983), and that they are coupled to adenylate-cyclase mediating both chronotropic and contractile effects (Ask et al. 1985; Bristow et al. 1986; Brodde et al. 1984; Gille et al. 1985). These in vitro findings have been supported by studies in humans showing that cardiac ~2-receptors are functionally active and responsible for heart rate and inotropic responses to ~2-agonists (Arnold et at. 1985; Hall et al. 1989; Lipworth et al. I 989a). There are a number of other bronchial ~2mediated effects in addition to smooth muscle relaxation (see table I). It is important to appreciate that bronchial smooth muscle does not receive any direct sympathetic innervation as such. This is consistent with the hypothesis that ~2-receptors are of the humoral type normally accessible to circulating adrenaline but not noradrenaline (Ariens & Simonis 1983).

Table I. Site and action of human i3-adrenoceptors

Tissue

Receptor

Heart Airways

Effects Inotropic. chronotropic Smooth muscle relaxation . Prejunctional inhibition of cholinergic neurotransmission. Decreased bronchial hyperreactivity. Increased mucociliary clearance. Reduction in mucosal oedema. Inhibition of mediator release.

Lungs Blood vessels Skeletal muscle Uterus Leucocytes. erythrocytes. platelets Liver. pancreas

i31 i32 i32 i32 i32

Kidney

i32

Adipose tissue

i33

i32

? Vasodilatation Finger tremor. hypokalaemia Relaxation ?

Increased release of glu. lact. pyr. ins. HDL Increased excretion of Mg. Ca.P04 Thermogenesis. lipolysis

= glucose; lact = lactate; pyr = pyruvate; = insulin; HDL = high density lipoprotein; Mg = magnesium;

Abbreviations: glu

ins Ca

= calcium; P04 = phosphate.

1.3 In Vitro Selectivity of ~2-Agonists The evaluation of selectivity has conventionally been based on the relative effects of ~-agonists on isolated guinea-pig atrial (~d and tracheal (~2) preparations. Potency refers to the concentration of agonist producing 50% of the maximal response (EC50), as assessed from dose-response curves. Selectivity is derived by comparison of EC50 values for the relative effects of an agonist on ~1- and ~2mediated responses. At equimolar concentrations, fenoterol exhibits a 2.7-fold greater potency for tracheal ~2-receptors than salbutamol (O'Donnell & Wanstall 1978). Selectivity ratios (as ~2: ~1) show that fenoterol and salbutamol are 59 and 107 times more selective for ~2-receptors than isoprenaline (O'Donnell 1972). This implies that salbutamol exhibits a 1.8-fold greater selectivity for ~2-receptors, relative to fenoterol. Other studies have shown se-

57

Risks and Benefits of i32-Agonists

lectivity ratios for fenoterol and terbutaline of 102 and 182 compared with isoprenaline (O'Donnell & Wanstall 1974). In guinea-pig trachea both fenoterol and salbutamol act as full agonists, whereas in atria salbutamol behaves as a partial agonist (Wagner et al. 1973). In summary, the in vitro selectivity of fenoterol for i32-receptors is considerably greater than that of isoprenaline, but slightly less compared with terbutaline and salbutamol.

1430 1230

g 1030

:> w u.

E

5

'"

3

'x

E £

-~

o

Z

o o

FEVl sGaw

4

2 1

0

100

200 500 1000 2000 4000 Cumulative salbutamol dose ~9)

Fig. 3. Number of patients who achieved maximum airway response at each dose of inhaled salbutamol, for FEV I and specific airway conductance (sGaw) [from Lipworth et al. 1988, with permission].

Drug Safety 7 (1) 1992

58

6 Salbutamol

o -1

---'r---r----x---r----r---.LPlacebo I

100

I

1000

I

10000

Cumulative salbutamol dose v.g)

Fig. 4. Cumulative log dose-response curve for changes in specific airway conductance (sGaw) in healthy subjects given inhaled salbutamol 100 to 4000/Lg or placebo (from Lipworth et al. 1989c, with permission).

a percentage of predicted FEY 1 when comparing bronchodilator responsiveness, in order to account for individual differences in airways geometry (Tinkelman et al. 1977; Weir & Sherwood-Burge 1991). In healthy subjects given an identical dose protocol of inhaled salbutamol (Lipworth et al. 1989c), unlike asthmatic responses, a plateau in bronchodilatation occurred at a dose of 100~g (fig. 4). This might suggest that asthmatics are less sensitive to inhaled f:12-agonists, although direct comparison between healthy and asthmatic airways is complicated by differences in baseline airway geometry. In vitro studies with asthmatic human bronchial muscle have not shown any evidence of altered f:12responsiveness (Whicker et al. 1988). It is, however, conceivable that the initial few doses of inhaled salbutamol are required to open up the more narrowed asthmatic bronchi, in order to allow peripheral access to subsequent doses. Alternatively, higher doses may be required in asthmatic bronchi because of impaired accessibility to the muscle f:12receptor through the inflamed mucosa. What is the clinical relevance of these dose-response relationships? The optimisation of bronchodilator response is more important for those patients with more severe airflow obstruction in whom conventional doses of bronchodilator therapy are unhelpful. In everyday clinical prac-

tice, shortened dose-response curves using inhaled salbutamol 200 and lOOOlLg would identify those who respond to higher doses, and would add only L5 min on to a standard reversibility test. Improvements in airways response with higher doses of inhaled f:12-agonist may be offset by associated extrapulmonary adverse effects. It should, however, be emphasised that most asthmatic patients may be controlled by an optimised dose of inhaled steroids, with inhaled .82-agonists being used as required for relief of symptomatic wheeze.

3. Systemic Effects Dose-related improvements in airways response with inhaled f:12-agonists are also accompanied by dose-dependent systemic adverse effects which are mediated by extrapulmonary .82-receptors. These include finger tremor, hypokalaemia, electrocardiographic sequelae and chronotropic and inotropic responses (Lipworth et al. 1988, 1989c,d) [fig. 5]. Dose-response curves for inhaled salbutamol show that systemic effects are not present until after the 500ILg dose, and then occur in linear dose-dependent fashion. Systemic absorption occurs primarily across the lung-vascular bed (Collier et al. 1980; Kung et al. 1987; Lipworth et al. 1989d), and hence compounds which are more lipophilic, such as fenoterol, are absorbed to a greater degree (Deenstra et al. 1988; Jeppsson et al. 1989). 3.1 Hypokalaemic and Electrocardiographic Effects Hypokalaemic effects of inhaled .82-agonist therapy occur as a result of an intracellular shift of potassium into skeletal muscle, due to stimulation of membrane-bound Na+/K+-ATPase (Brown et al. 1983; Lipworth et al. 198ge). Electrocardiographic changes which are known to be associated with hypokalaemia include T wave inversion, ST depression and U waves, but not QT prolongation (fig. 6) [Shamroth 1982; Surawicz 1967; Weaver & Burchell 1960). Hypomagnesaemia may cause prolongation of the QT interval, although falls in serum magnesium in response to inhaled f:12-agonists are

59

Risks and Benefits of f32-Agonists

300

...=

Salbutamol

Finger tremor

250 200

~ 150 .

-------.

.= D=

Tremor

7

o

Jl

IJJ

3

PL

6 5

ai:::> 4 g 3

at 2

1

o

0

IJJ~

D=

3

4

LOS

HOS

~

Severity of symptoms

Fig. 9. Frequency and severity (0 to 5) of subjective palpitations and tremor after a cumulative dose of inhaled salbutamol 40001Lg, following 2 weeks of treatment with either placebo (PL), low-dose inhaled salbutamol (LOS) or high-dose inhaled salbutamol (HOS) [after Lipworth et al. I 989g].

4.3 Corticosteroid Effects The effects of corticosteroids in acute asthma are thought to be due to their anti-inflammatory properties, which do not occur for at least 12h. EIlul-Micalef et al. (1975) showed rapid reversal of resistance to isoprenaline-induced bronchodilatation, within Ih of corticosteroid administration. Prednisolone has been shown to increase lymphocyte !12-receptor density within 16h in asthmatic patients receiving !12-agonists, to levels found in healthy controls (Brodde et al. 1988). This increase in density appeared to be mirrored by increased bronchodilator responsiveness to inhaled salbutamol. The clinical impression that intravenous hydrocortisone has a beneficial effect within the first few hours might conceivably be explained by increased sensitivity of bronchial i32-receptors to inhaled !12-agonist, although this hypothesis remains unproven. However, !12-receptor up-regulation does not appear to occur with inhaled steroids, since high-dose beclomethasone dipropionate given for

4 weeks has no effect on the bronchodilator doseresponse curve for inhaled salbutamol (Molema et al. 1988).

5. Disease Control Single doses of inhaled !12-agonists have a protective effect against histamine-induced bronchial hyperreactivity, and this appears to be independent of the effect on airway calibre (Britton et al. 1988). However, after a 2-week period of repeated doses of inhaled terbutaline, the protection against bronchial hyperreactivity to histamine is attenuated, in contrast to the preserved bronchodilator response (Vathenen et al. 1988). Furthermore, there is a rebound increase in bronchial hyperreactivity after withdrawal of inhaled terbutaline. Two other studies which compared the effects of inhaled terbutaline and budesonide given for up to 6 months showed a small increase in bronchial hyperreactivity with terbutaline, in contrast to a decrease with budesonide (Kerrebijn et al. 1987; Kraan et al.

Risks and Benefits of 112-Agonists

1985). Van Schayck and coworkers (1990) showed that treatment with salbutamol for 12 months resulted in a small increase in bronchial hyperreactivity, whereas bronchodilator responsiveness and lymphocyte i32-receptor density were unchanged. It remains unclear whether the magnitude of these changes in bronchial hyperreactivity are of any clinical relevance in terms of long term disease control. In a recent crossover study from New Zealand (Sears et al. 1990), regular use of inhaled fenoterol 1600J'g daily for 6 months resulted in a deterioration of various parameters of asthma control in comparison with occasional usage. This appeared to be independent of concomitant inhaled steroid therapy. However, increased airway reactivity to methacholine occurred in only 34% of cases taking regular compared with intermittent inhaled 132agonist therapy, and changes in reactivity were of small magnitude, suggesting that other factors may have been more important in causing a deterioration in control. There is evidence to suggest that greater airways accessibility to inhaled antigen from regular i32-agonist therapy might have been responsible for causing increased airway inflammation and reactivity, and hence worsening asthma control (Lai et al. 1989). If this is the case, then inhaled i32-agonists with a longer duration of action might perhaps be expected to be more harmful in this respect. Page (1991) has hypothesised that inhaled i32-agonists might have adverse effects on asthma control due to their inhibitory activity against the body's own natural anti-inflammatory mechanisms. This might result in long term injury to the bronchial mucosa and persistent airway hyperreactivity, and particularly so if the protective effects of steroids are not present.

6. Novel {j2-Agonists The novel, long-acting inhaled i32-agonists salmeterol and formoterol have stimulated considerable interest, and merit separate discussion. Both drugs cause bronchodilatation for up to 12h, and have been shown to produce prolonged effects in nocturnal and exercise-induced asthma (Maesen et

65

al. 1990a,b; McAlpine et al. 1990; Newnham et al. 1991; Ullman et al. 1988). However, an important difference between the 2 drugs is that salmeterol takes much longer to reach peak effect than does formoterol. The pharmacological properties of salmeterol may be explained by the molecular configuration of its long amine head, which may be involved in hydrophobic interactions in the core of the receptor protein, resulting in high affinity binding (Jack 1991). Furthermore, unlike salbutamol, salmeterol associates with the i32-adrenoceptor complex slowly and does not dissociate (Bradshaw et al. 1987). The high degree of lipophilicity of salmeterol may also determine its duration of action due to its retention in tissue (Jeppsson et al. 1989). The latter explanation would also hold good for formoterol, whereas the presence of exoreceptor binding with formoterol is less likely to be due to the small size of its amine head. The recent findings of Twentyman et al. (1990) are of particular interest, in that inhaled salmeterol protected against both the early and late phases of allergen-induced bronchoconstriction, as well as inhibiting allergen-induced bronchial hyperreactivity over the same period (up to 34h). The late asthmatic response to allergen challenge is thought to be a consequence of airway inflammation, predominantly involving eosinophil influx and activation, in contrast to the early phase which is caused by bronchospastic mediators released from IgE-triggered mast cells. Inhaled salbutamol is a potent inhibitor of mast cell degranulation and abolishes the early, but not the late, bronchoconstrictor response to allergen (Cockcroft et al. 1987; Howarth et al. 1985). However, the protective effect of salmeterol against the late allergen response (Twentyman et al. 1990) may simply reflect the longer duration of bronchial smooth muscle relaxation, as opposed to any true anti-inflammatory properties (Britton et al. 1991; Rogers et al. 1991). This hypothesis is also supported by data showing that there is no difference between inhaled salmeterol and salbutamol 4h after allergen challenge in terms of suppression of in vivo inflammatory mediator release, despite more prolonged protec-

66

tion against allergen-induced bronchoconstriction with salmeterol (O'Shaughnessy et al. 1991). There are, however, in vitro data to show that salmeterol inhibits the release of proinflammatory mediators from mast cells (Butchers et al. 1987) and alveolar macrophages (Baker et al. 1990). From the data that are available it is too early to say whether salmeterol possesses any useful anti-inflammatory activity. Such claims should not result in the prescribing of salmeterol as first-line disease modifying therapy instead of inhaled steroid. There are only a few published papers on the dose-response relationships between airway and systemic effects of inhaled long-acting .82-agonists. Ullman et al. (1988) showed minimal differences in peak and duration of bronchodilator responses between 50, 100 and 200J.Lg doses of inhaled salmeterol, and a small increase in heart rate (6 beats/ min) was seen only with the 200J.Lg dose. Dose-ratios (compared with placebo) for finger tremor were 1.4 for salbutamol 200J.Lg and 2.2 for salmeterol 200J.Lg. Comparison of dose-response curves in 9 asthmatic patients (Lofdahl & Svedmyr 1989) showed that a cumulative dose offormoterol 123J.Lg produced a peak bronchodilator response equivalent to that of salbutamol 1300J.Lg. The same doses of salbutamoland formoterol caused mean heart rate increases of 5 beats/min, and finger tremor dose ratios of 1.7 and 3, respectively. The small magnitude of these extrapulmonary effects in the above 2 studies is probably a reflection of systemic tachyphylaxis from previous .82-agonist exposure, rather than specific properties of salmeterol or formoterol. It remains unclear whether bronchodilator tolerance develops with the novel long-acting inhaled .82-agonists. It is conceivable that prolonged receptor occupancy might result in a greater propensity to cause down-regulation or G protein uncoupling of airway .82-receptors. Ullman et al. (1990) showed no attenuation of bronchodilator response to inhaled salbutamol after treatment for 2 weeks with either inhaled salmeterol 50J.Lg twice daily or salbutamol 200J.Lg 4 times daily in a crossover study with 12 stable asthmatic patients. The study was flawed by the absence of a washout period without

Drug Safety 7 (I) 1992

.82-agonists prior to each treatment phase, and it is therefore possible that previous .82-agonist exposure might have caused .82-receptor down-regulation prior to the study. This would also explain why tachyphylaxis of tremor responses did not occur, when comparing dose-response curves before and after treatment with salmeterol or salbutamol. Arvidsson et at. (1989) also found no evidence of bronchodilator tolerance in a study comparing dose-response curves to inhaled salbutamol, before and after 2 weeks' treatment with inhaled salbutamol 200J.Lg twice daily or formoterol 12J.Lg twice daily in 20 asthmatic patients. However, the I-week duration of washout between treatments was almost certainly too short to prevent any carry-over down-regulation effect. Furthermore, previous exposure to regular .82-agonists without a run-in period might also have produced down-regulation prior to the initial treatment period. Finally, in a third study comparing 4 weeks of treatment with inhaled formoterol 24J.Lg twice daily or salbutamol 400J.Lg twice daily, the bronchodilator response to salbutamol was unimpaired, although only the response to a single dose of salbutamol 400J.Lg was assessed, and not a full dose-response curve (Wallin et al. 1990). Failure to include a run-in or washout phase also limits its interpretation. Studies which to date have only been published in abstract form h~ve shown that disease control and bronchodilator efficacy are maintained for 3 months with salmeterol (Britton et al. 1990; Dahl 1989; Viskum 1990) and for up to 12 months with formoterol (C1auzel et al. 1990; Rosenhall et al. 1990), although full dose-response curves do not appear to have been evaluated.

7. Conclusions The use of conventional low doses of inhaled .82-agonists provides effective bronchodilatation without systemic adverse effects. Patients with more severe asthma may benefit from higher than conventional doses. At these higher doses, systemic .82effects occur which appear to be greater with fenoterol than with salbutamol or terbutaline, although there is no evidence that the former is any

Risks and Benefits of Ih-Agonists

less Ih-selective. Tolerance develops to systemic responses but not to bronchodilator responses during long term inhaled Ih-agonist therapy. The recent findings of increased airway hyperreactivity and worsening disease control with regular inhaled Ih-agonist therapy underline the need for careful reappraisal of the use of these agents in asthma, including the role of the newer long-acting drugs. Patients who require regular use of inhaled .62-agonists should be given additional anti-inflammatory therapy with inhaled corticosteroids.

Acknowledgements The authors wish to thank Mrs Joy Thomson for typing the manuscript.

Addendum Since this article was written, Newnham et al. (1992) have for the first time compared the tl2-adrenoceptor selectivity of inhaled salbutamol and fenoterol at equal doses by weight (I and 4mg) in healthy volunteers in a doubleblind crossover study, after pretreatment with placebo or atenolol 25mg in order to dissect out til effects. Atenolol produced a mean reduction in exercise heart rate of 21 % (i.e. substantial til-blockade) and caused a small degree of attenuation of hypokalaemia and tremor in response to fenoterol and salbutamol (i.e. tl2-blockade). Fenoterol caused slightly greater tl2-mediated effects than salbutamol, although even with the 4mg dose differences were not clinically relevant. Fenoterol produced equivalent chronotropic (heart rate), inotropic (Doppler stroke distance) and eiectrocardiographic (T wave and QTc) effects in comparison with salbutamol, at both doses. The degree of tl2-blockade exhibited by atenolol closely mirrored the blunting of systolic blood pressure (SBP) in response to fenoterol and salbutamol, implying that the SBP response was also tl2-mediated. Furthermore, atenolol did not significantly attenuate the inotropic response to either drug at the 5mg dose. The findings, therefore, suggest that the tl2-selectivity of inhaled fenoterol, like salbutamol, is retained even at a higher than conventional dosage.

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Risks and Benefits of {h-Agonists

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Correspondence and reprints: Dr Brian J. Lipworth, Department of Ginical Pharmacology, Ninewells Hospital and Medical School, Dundee 001 9SY, Scotland.