Contents

Drug Evaluation

Drugs 38 (I): 77-1 22, 19890012-6667/89/0001-0077/$23.00/0© ADiS Press LimitedAll rights reserved.DREND237

Salbutamol in the 1980sA Reappraisal of its Clinical Efficacy

Allan H. Price and Stephen P. ClissoldADI S Dru g Information Services, Auckland, New Zealand

Various sections of the manuscript reviewed by: G.M. Cochrane, Department ofT hora cicMedicine, Gu y's Hospi tal , London, England; G.K. Crompton, Respirat ory Unit, NorthernGeneral Hospital, Edinburgh, Scotland; S. Godfrey, Department of Pediat rics, HadassahUniversity Hospital, Mount Scopus, Jerusalem, Israel ; I. Gregg, Department of PrimaryMedical Care, University ofSouthampton, England; J. W. Jenne, Pulmonary Section , Vet­erans Adm inistration Hospital, Hin es, Illinois, USA; G. Louridas, Cardiovascular Clinic,Ahep a Hospital, Thessaloniki, Greece; T. Morooka , School of Med icine, Fukuoka Uni­versity, Japan; A.E. Tattersfield, U niversity of Nottingham, Respiratory Med icine Unit,City Hospital, Nottingham, England ; J.B. Toogood, Allergy Clinic, Victo ria Hospital ,London , On tario, Canada .

Summary 78I. Pharmacodynam ic Properties 82

1.1 Bronchial Effects 821.2 Cardiovascular Effects 83

1.2.1 Studies in Healthy Volunteers 831.2.2 Studies in Patients with Reversible Obstructive Airways Disease 831.2.3 Studies in Patients with Cardiovascular Disease 83

1.3 Uterine Effects 841.4 Metabolic Effects 85

1.4.1 Potassium Metabolism 851.4.2 Lipid Effects 851.4.3 Glucose and Insulin Effects 861.4.4 Effects on Fetal Metabolism 86

1.5 Effects on the Central Nervous System 861.6 Inhibition of Allergic Responses 86

1.6.1 In Vitro Studies 861.6.2 Studies in Healthy Volunteers 871.6.3 Studies in Asthmatic Patients 87

1.7 Effects on Ciliary Activity 871.8 Mechanism of Action 87

2. Pharmacokinetic Studies 892.1 Absorption 892.2 Distribution 902.3 Metabolism and Eliminat ion 91

2.3.1 Elimination Half-Life 912.4 Pharmacokinetics of Salbutamol in Pregnancy 912.5 Controlled Release Preparation s 92

78

Synopsis

Drugs 38 (/) /989

3. Therapeutic Trials in Respiratory Diseases 923.1 Influence of Formulation on the Efficacy of Salbutamol 93

3.1.1 Inhaled Salbutamol 933.1.2 Nebulised Salbutamol 943.1.3 Oral Salbutamol 943.1.4 Parenteral Salbutamol 953.1.5 Inhaled Versus Nebulised Salbutamol 953.1.6 Inhaled Versus Oral Salbutamol 95

3.2 Use in Reversible Obstructive Airways Disease 963.2.1 Comparisons with Placebo 963.2.2 Comparisons with Other Ih-Agonists 963.2.3 Comparisons with Anticholinergic Drugs 1003.2.4 Comparisons with Methylxanthine Derivatives and Their Use in

Combinat ion 1013.2.5 Salbutamol in Combination with Beclomethasone Dipropionate 1023.2.6 Comparisons with Other Drugs and/or Their Use in Combination 102

3.3 Use in Severe Acute Asthma 1033.3.1 Nebulised and Parenteral Salbutamol 1033.3.2 Compar isons with Other Drugs and/or Their Use in Combination 104

3.4 Use in Childhood Asthma 1043.4.1 Comparisons with Placebo 1043.4.2 Comparisons with Other Ih-Agonists 1063.4.3 Comparisons with Other Drugs and Their Use in Combination 106

3.5 Use in Exercise-Induced Asthma 1084. Therapeutic Trials in Preterm Labour 1095. Adverse Effects 110

5.1 Cardiovascular-Related Adverse Effects 1105.2 Tremor 1115.3 Adverse Metabolic Effects : 1115.4 Tolerance 111

6. Dosage and Administration 1137. Place ofSalbutamol in Therapy 113

Summary

Salbutamol (albuterol) is a fJ2-selective adrenoceptor agonist which accounts for itspronounced bronchodilatory, cardiac, uterine and metabolic effects.

Duringthe intervening yearssince salbutamol wasfirst reviewed in the Journal(1971),it has become extensively used in the treatment of reversible obstructive airways disease.Numerous studies in this disease (including severe acute, childhood and exercise-inducedasthma)haveconfirmedthe bronchodilatory efficacy ofsalbutamol, and it has been shownto be at least as effective as most of the currently available bronchodilators, if not moreeffective.

The onset ofmaximum effect ofsalbutamol is dependent on the formulation used andthe route by which it is administered. In most patients inhaled salbutamol is a first-linetherapy, since it offers rapid bronchodilation, usuallyrelieving bronchospasm within min­utes. Although oral salbutamol has often proved to be less efficacious than the inhaledformulation, it still affords clinically significant bronchodilation, and it is particularlyuseful in those patients unable to coordinate the use of inhalers. Parenteralformulationsof salbutamol are generally reserved for the treatment of severe attacks of bronchospasmand they are one of the treatments ofchoice in these life-threatening situations.

Studies of the concomitant use ofsalbutamol and other agents such as anticholinergics,

Salbutam ol: A Reappraisal 79

methylx anthines and beclomethasone dipropionate have usually shown a complementaryresponse in the majority ofpatients, as might be expected from the different mechanismsof action of these groups of drugs.

Salbutamol is generally well tolerated and any side effects observed are a predictableextension of its pharma cology. Since the frequency of side effects is dose related, andtherefore dependent on the route ofadministration, it is not surprising that they are muchmore common following intravenous and oral rather than inhalation therapy. Tremor,tachycardia and hypokalaemia are the most frequently reported adverse effects.

After nearly 20 years ofuse, salbutamo l is well established as a 'first-choicetreatmentin reversible obstructive airways disease. Indeed, throughout this time many new bron­chodi/atory agents have been studied but none have proved more effective. Clinical eval­uation of salbutamol in the treatment of premature labour, hyperkalaemia and cardiacfailure awaits f urther studies, although to date some encouraging results have been re­pon ed .

Pharmacodynamic Studies Salbutamol is a Ih -selective adrenoceptor agonist which has demonstrated consider-able bronchodilatory effects. In studies in healthy volunteers, inhaled salbutamol causeda rapid and significant bronchodilation by reducing bronchomotor tone in both the largeand small airways, as reflected by increases in sGaw, FEYI, FEF25_75, FEF50, FEY3,

FEF75-88 and FEF75, and effectively inhibited histamine-induced bronchospasm. As wouldbe expected, the bronchodilatory effects of salbutamol are greatly dimin ished followingcoadm inistration of non-selective {3-blockers such as propranolol, betaxolol and tertatolol.The selective {3-blocker atenolol had no such effect. Lower doses of inhaled salbutamolare required to bring about maximum bronchodilation in normal volunteers than inasthmatic patients . Although salbutamol has effective antitussive propertie s, its clinicalapplication in this area requires further investigation.

In common with other {32-adrenoceptor agonists, salbutamol demon strated vasodi­latory and inotropic effects in healthy volunteers , and in patients with reversible obstruc­tive airways disease or cardiovascular disease, particularly after intravenous administra­tion. However, the clinical efficacy of salbutamol in the treatment of heart failure remainsto be established.

Intra venous salbutamol causes a marked reduction in uterine tonicity in women suf­fering from prima ry dysmenorrhoea, and this was associated with pain relief in preg­nancy. Furthermore, salbutamol by intravenous infusion reduced uteroplacental bloodflow by 18 to 50%.

Salbutamol exerts a number of metabolic effects. Intra venous and nebulised salbu­tamol decrease serum potassium concentrations, although the effect is generally mild andtransient. However, intra venous salbutamol has been used to treat hyperkalaemia in renalfailure patients. Salbutamol possesses lipolytic activity which is manifested as significant

.increases in non-esterified fatty acid and high density lipid-cholesterol. Oral and intra­venous salbutamol cause increases in blood glucose and insulin , by stimulating glyco­genolysis in the liver and having a direct stimulatory effect on {32-receptors in insulinsecretory pancreas cells. Studies in animals and humans indicate that maternally ad­ministered salbutamol exerts some effects on fetal metabol ism, but the only change re­ported to date which could be of clinical significance is an increase in growth hormonelevels.

Salbutamol possesses antidepressant propert ies, although the mechan ism by which itexerts this activit y is unclear. Other reported eNS effects in animals include anorexia,induced by mechanisms involving {3-adrenergic sites in the brain of rats, and increasedvasopressin levels in the cerebrospinal fluid of dogs.

Salbutamol has demonstrated some antiallergic activit y. In vitro, salbutamol producesdose-related inhibition of histamine release from lung fragments. However, it has littleor no effect on allergen-induced histamine release from leucocytes obta ined from allergicpatients and only weak activity at inhibiting ant i-IgE-induced histamine release from

80

Pharmacokinetic Studies

Therapeutic Studies

Drugs 38 (1) J989

human skin slices. Inhaled and oral salbutamol are potent inhibitors of mast cell mediatorrelease; in addition, both effectively inhib it inhaled allergen-induced bronchoconstriction.

As with other Ih-adrenoceptor agonists, salbutamol stimulates mucus secretion andmucociliary transport. Nebulised solutions of salbutamol increase mucociliary rates byup to 36% in obstructive airways disease patients and 16% in healthy volunteers .

The mechanism of action of salbutamol is thought to be mediated via the stimulationof the production of cyclic adenosine-3' 5'-monophosphate (cAMP) by activation of theenzyme adenyl cyclase. Cyclic AMP is then capable of triggering a sequence of intra­cellular events that ultimately leads to the physiological effects associated with salbutamoltherapy.

Despite its widespread use, pharmacokinetic information on salbutamol is limited,particularly with respect to newer formulations, and further studies are needed to fullydefine its pharmacokinetic profile in humans. The major portion of an inhaled dose ofsalbutamol is swallowed and handled orally; the small fraction that is delivered to thelung (approximately 10%) rapidly appears in the circulation as free drug. Salbutamol iswell absorbed following oral administration, with peak plasma concentrations occurringbetween I and 4 hours later. However, due to extensive presystemic metabolism in thegut wall its systemic bioavailability is only 50%. After multiple oral doses of salbutamol4mg 4 times daily, steady-state plasma concentrations are attained by the third day ofadministration. Additionally , salbutamol 2mg 4 times a day was found to be bioequi­valent to a controlled release formulation given at a dosage of 4mg twice daily over a5-day period.

In animal studies it has been shown that salbutamol is rapidly cleared from all tissues.In addition, the drug undergoes placental transfer from maternal to fetal plasma, andslightly penetrates the blood-brain barrier . The apparent volume of distribution of sal­butamol in humans is 156L, indicating extensive extravascular uptake. The plasma pro­tein binding of salbutamol over the concentration range 0.05 to 2.0 mg/L is 7 to 64%.The blood/plasma concentration ratio of salbutamol is about I.

Salbutamol and its metabolite(s) are rapidly excreted in the urine and faeces, withabout 80% of a dose being recovered in urine within 24 hours, irrespective of the routeof administration.

Unchanged salbutamol accounts for approximately 30%of the excreted dose followingoral and inhaled administration, and about 65% after intravenous administration. Un­changed salbutamol appears to undergo active tubular secretion. Salbutamol is almostexclusively metabolised by conjugation to a 4'-O-sulphate ester in the gastrointestinaltract and liver. The metabolite possesses little or no ~-adrenergic activity. The eliminationhalf-life of salbutamol is 2.7 to 5.5 hours after oral and inhaled administration, and 2.4to 4.2 hours after intravenous administration. The pharmacokinetic profile of salbutamolwas generally very similar in patients receiving the drug for prevention of preterm labour,although renal clearance was significantly lower.

Many short and several long term studies have confirmed the therapeutic efficacy andgood tolerability of salbutamol in reversible obstructive airways disease irrespective ofthe formulation or route of administration. Single and multiple doses of salbutamol weresignificantly superior to placebo in terms of improving respiratory function and, overall,inhaled salbutamol (usually 200 or 400llg) would seem to be the formulation of choicefor the majority of patients with reversible obstructive airways disease. Inhalation pro­duces peak bronchodilation within 10 minutes and the improvement in lung functionhas been reported to last for up to 6 hours . A similar bronchodilatory effect is obtainedwith nebulised salbutamol (usually 2.5mg); indeed, no significant difference was observedbetween inhaled and nebulised salbutamol , although a greater incidence of dose-relatedadverse effects occurred with the nebulised formulation. Peak bronchodilation after oralsalbutamol (most frequently 4mg) usually occurred at about 2 hours, and lasted for upto 8 hours. After parenteral administration of salbutamol , rapid and effective broncho-

Salbutamol: A Reappraisal

Adverse Effects

81

dilation occurred within 15 minutes and lasted for up to 3 hours , but this route of admin­istration is often associated with cardiovascular-related side effects and is reserved fortreating life-threatening attacks of severe acute asthma. :A large number of short termstudies comparing the efficacy of salbutamol and alternative bronchodilators in patientswith reversible obstructive airwa ys disease have been reported. Salbutamol was moreeffective than isoprenaline and isoetharine, and in general there were no major clinicaldifferences compared with bitolterol, broxaterol, c1enbuterol, fenoterol , orciprenaline(metaproterenol), procaterol, terbutaline and tulobuterol. Although some of these agentshad longer durations of action than salbutamol, this was often offset by the rapid onsetof bronchodilation and fewer adverse effects associated with the latter drug. In single­dose trials comparing salbutamol and anticholinergic drugs in reversible obstructive air­ways disease , salbutamol was superior to atropine methonitrate and oxitropium, equiv­alent to atropine and ipratropium bromide, but , as might be expected, inferior to ipra­tropium bromide administered in combination with the ,82-adrenoceptor agonist fenoterol.There have been few well-designed clinical trials comparing salbutamol with methylxan­thine therapy in the long term management of reversible obstructive airways disease. Inthose studies that have been reported, usual oral doses of salbutamol (4mg 3 times daily)appeared to be as effective as oral aminophylline, choline theophyllinate and a combin­ation of theophylline and hydroxyzine.

Studies evaluating the efficacy of salbutamol in combination with anticholinergic drugsor other agents such as theophylline or beclomethasone dipropionate have generally re­corded superior improvements with combination therapy compared with the individualcomponents alone , but such differences were not always statistically or clinically sig­nificant. Further well-designed studies are needed to confirm the apparent improvementin efficacy associated with combination therapy and to determine the most appropriatedosages for obtaining the greatest benefit.

Clinical studies in patients with severe acute asthma have confirmed that both ne­bulised and parenteral salbutamol are efficacious and relatively safe. Indeed, comparativestudies in patients with severe acute asthma have shown that salbutamol is more effectivethan adrenaline (epinephrine) or aminophylline and equall y as effective as terbutalineand ipratropium bromide.

Salbutamol has been successfully used in the treatment of childhood asthma and inshort and long term studies it improved respiratory function to a significantly greaterextent than placebo. Other comparative studies demonstrated that salbutamol was su­perior to isoprenaline, and at least as effective as terbutaline and fenoterol. Combinationtherapy with salbutamol and theophylline or ipratropium bromide was generally syner­gistic in childhood asthma.

Salbutamol administered by inhalation is a very effective agent in the prophylaxis ofexertional asthma. In terms of protection against exercise-induced asthma, inhaled sal­butamol was superior to sodium cromoglycate, theophylline, orciprenaline and ipratrop­ium bromide, and it was at least as effective as terbutaline and fenoterol.

Clinical evaluation of salbutamol in the treatment of premature labour has tended tobe of a preliminary nature, generally in uncontrolled trials. Firm conclusions regardingits relative efficacy await further research , although some encouraging results have beenreported.

Salbutamol is a well-tolerated treatment for the majority of patients suffering fromreversible obstructive airwa ys disease. The most common adverse effects are dose related,and therefore dependent upon formulation and route of administration, and are char­acteristic of the sympathomimetic agents. Usual inhaled doses of salbutamol do not ap­pear to produce significant adverse reactions. The principal adverse effects of the drugare mild skeletal muscle tremor and cardiovascular-related effects, including tachycardia,palpitations and peripheral oedema. Reported metabolic adverse effects include signifi­cant increases in plasma glucose and insulin, and dose-related decreases in plasma po­tassium concentrations, especially following intravenous therapy. The decrease in potas-

82 Drugs 38 (1) 1989

sium concentrations is usually transient and supplemental potassium therapy is rarelyrequired. The weight of evidence suggests that absolute clinical tolerance to the bron­chodilatory effects of salbutamol does not develop, although someattenuation of bron­chodilatory response has been documented.

Dosage and Administration Salbutamol is available in a wide range of formulations for the management of thevarious forms of reversible airways disease (in infants, children and adults)and threat­ened premature labour. The recommended dosage instructions are summarised in tableVIII in section 6.

Salbutamol was first reviewed in the Journal in1971 (Vol. I, No.4, pages 274-302). During theintervening period it has been extensively inves­tigated and become well established in the treat­ment of certain respiratory diseases. This reap­praisal of salbutamol is based almost entirely onthe literature published during the I980s.

1. Pharmacodynamic Properties

Salbutamol (albuterol) is a long-acting ,62-selec­tive adrenoceptor agonist which has demonstratedbronchodilatory, cardiovascular, uterine and meta­bolic effects in humans. ,62-Receptor selectivity isobtained by modifying the basic catechol structurecommon to the naturally occurring adrenergicneurotransmitters adrenaline (epinephrine) andnoradrenaline (norepinephrine) [fig. I].

Salbutamol is a saligenin derivative, rather thana catechol , and in common with other selective ,62­agonists (fenoterol, pirbuterol, etc.), it has negligi­ble o-adrenoceptor stimulatory properties. Fur­thermore, its,61 effects are minimal compared withits ,62 effects and, consequently, salbutamol pref­erentially stimulates receptors in the respiratorysystem, uterus and skeletal muscle.

1.1 Bronchial Effects

Studies in healthy volunteers have clearly shownthat salbutamol causes large airways dilatation,probably by reducing bronchomotor tone , as in­dicated by increases in specific airways conduct­ance (sGaw) and forced expiratory volume (FEV I)[Macnee et al. 1982; Riedel & Van der Hardt 1986;Sorbini et al. 1984]. There is also evidence that it

Noradrenaline

Adrenaline

HO~ 9H3

HOHC~9H-eH2NH-9-CH32 OH CH3

Salbutamol

Fig. 1. Structural formulae of salbutamol and the naturaladrenoceptor agonists adrenaline (epinephrine) and nor­adrenaline (norepinephrine) .

produces an improvement in small airways func­tion as estimated by forced expiratory flow at 25%(FEF2S) and 75%(FEF7S) of vital capacity, and peakexpiratory flow (PEF) [Riedel & Van der Hardt1986; Sorbini et al. 1984].

In addition, studies in both healthy volunteersand patients with asthma have shown that inhaledsalbutamol 200/lg is more effective in blockinghistamine-induced bronchospasm than intraven­ous aminophylline 670mg (Jones et al. 1987) andequivalent to oral atropine 4mg (Chung et aI. 1982).

As would be expected, a number of studies inhealthy volunteers have shown that the broncho­dilatory effects of inhaled salbutamol 200 or 400/lgare greatly reduced or abolished following thecoadministration of the non-selective ,6-blockers

Salbutamol: A Reappraisal

propranolol, betaxolol and tertatolol (Desche et at.1987; Palminteri & Kaik 1983). However, coad­ministration of the selective {J-blocker atenolol100mg had no such effect (Desche et at. 1987).

It has been shown that lower doses of salbuta­mol are required to bring about maximum bron­chodilation in healthy rather than asthmaticsubjects. Barnes and Pride (1983) compared bron­chodilator dose-response curves to inhaled salbu­tamol in both normal and asthmatic subjects. Inthe healthy subjects, bronchodilation, measured bypartial expiratory flow volume, was achieved at acumulative dose of II O~g. The mean dose neces­sary to produce a half-maximal response (EDso)was 23~g. Not surprisingly in the asthmatic sub­jects maximal bronchodilation measured by FEV I

and by maximal flow volume curves was achievedat significantly higher (p < 0.01) doses of salbu­tamol, with a mean EDso of 83~g and a range of25 to 251~g.

The antitussive properties of a single oral doseof salbutamol 4mg have been studied and com­pared with those of various bronchodilators inhealthy volunteers with cough induced by inhala­tion of nebulised solutions of water and saline. Al­though pretreatment with salbutamol diminishedcough frequency, it was not as effective as inhaledfenoterol (360~g) or ipratropium bromide (Lowryet al. 1987). However , the clinical application ofsalbutamol as an antitussive agent remains to befully evaluated.

1.2 Cardiovascular Effects

As with other selective {J2-adrenoceptor stimu­lants, usual therapeutic doses of salbutamol ad­ministered by inhalation do not significantly affectthe cardiovascular system. However, particularlyafter parenteral injection or following administra­tion of large oral and nebuliseddoses, salbutamolmay cause more pronounced cardiovascular ef­fects. Such properties have been utilised to assessthe efficacy of salbutamol in heart failure, but atthe present time only a limited number oflong termstudies have been performed in this disease and

83

conclusions regarding the usefulness of salbutamolare not possible.

1.2.1 Studies in Healthy VolunteersSalbutamol administered intravenously or via

nebuliser caused a dose-related increase in heartrate (table I) and in systolic blood pressure (Coreaet at. 1984; Rolf Smith et at. 1984). Vascular {J2­adrenoceptor agonist effects were depicted by fallsin diastolic blood pressure of approximately 15%following 5 and lOmg doses of nebulised salbuta­mol (Rolf Smith et at. 1984), and up to about 42%following a 600~g intravenous dose (Corea et at.1984). Moreover, following intravenous adminis­tration (300 or 600~g), the velocity of circumfer­ential fibre shortening increased. However, in­creases in stroke index and ejection fraction weresmall; less than those seen following intravenousadministration of prenalterol I or 2mg (Corea etat. 1984).

1.2.2 Studies in Patients with ReversibleObstructive Airways DiseaseIn single-dose studies salbutamol was shown to

increase heart rate by 23% (p < 0.01) following almg inhaled dose (Kung et al. 1987) and by about28% following a single oral dose of 4mg (Winter etat. 1984). In this latter double-blind study, oral pir­buterol 15mg produced a similar increase in heartrate. In addition, right and left ventricular ejectionfractions were significantly increased by about 20and 13% following salbutamol and pirbuterol, re­spectively.

1.2.3 Studies in Patients withCardiovascular DiseaseThe cardiovascular effects of salbutamol have

been assessed in a variety of cardiovascular dis­eases including acute myocardial infarction, chronicheart failure, cardiogenic shock, etc. It is importantto note that many of these patients were very se­riously ill, therefore the findings reported belowmust be treated with caution .

Single oral doses and intravenous .infusions ofsalbutamol significantly increased heart rate inpatients with cardiovascular disease, however these

84 Drugs38 (1) 1989

Table I. Increases in heart rate in volunteers and patients following the administration of salbutamol (8), prenalterol (P), aminophylline

(Ap), vasoactive intestinal peptide (V), pirbuterol (Pb) and dobutamine (D)

Reference No. of pts 8tudy design Dosage, route Increase in heart rate

(%)

Studies in healthy volunteers

Corea et al. (1984) 7 r. sb, co S 300l'g IV 33.9

S 600l'g IV 63.0

P 1mg IV 11.7

P 2mg IV 22.6

Morice et al. (1986) 6 sb, co S 300l'g IV 21.0'

Ap 200 I'g/kg/min x 0.5h IV 10.8'V 60 pmol/kg/min x 0.5h IV 2.8

Rolf Smith et al. (1984) 9 r, sb, pc, co S 5mg Neb 30.6S 10mg Neb 42.8

Studies in obstructive airways disease

Dawson et al. (1982) 53 nb S 13 I'g/min IV (n 0= 31) 11.6'

S 13 I'g/min IV (n 0= 11) 10.0'

S 8mg PO (n 0= 11) 7.2'

Fowler et al. (1982) 9 sb, co S 10-40 ltg/min IV 13.3"

0250-750 I'g/min IV 10.3"

Kung et al. (1987) 8 nb S 1mg Inh 23.0'

Mettauer et al. (1985) 20 nb 8 6mg PO (n 0= 20) 5.4'8 6mg qid x 1 month PO (n 0= 12)

Mifune et at. (1982) 8 nb, pc 8 4-8mg PO 27.0"

Winter et al. (1984) 12 r, db, co 8 4mg PO 28.3Pb 15mg PO 22.7

Abbreviations: r 0= randomised ; sb 0= single-blind; db 0= double-blind; nb 0= non-blind ; co 0= crossover; pc 0= placebo-controlled;IV 0= intravenous ; Neb 0= nebulised; Inh 0= inhaled; PO 0= oral; qid = 4 times daily; , 0= P < 0.05; " 0= P < 0.Q1 .

increases were generally lower than those seen inhealthy volunteers (table I). Oral doses of 4 and8mg and intravenous infusions of 13 to 40 1tg/minsignificantly increased cardiac index by 21% to 53%(Dawson et al. 1982; Fowler et al. 1982; Mettaueret al. 1985; Mifune et al. 1982). Systemic vascularresistance was significantly reduced by between 12and 30% following administration of salbutamolorally or by intravenous infusion (Dawson et al.1982; Fowler et al. 1982; Mettauer et al. 1985).

1.3 Uterine Effects

Salbutamol is a moderately selective and potentinhibitor of tension development in the isolated ut­erus of term pregnant rats (Granger et al. 1985). In

ovariectomised postpartum rats, although salbu­tamol infusions of 2 1tgjkg/min produced initialmarked inhibition of uterine contractions, a sig­nificant but reversible tolerance to the inhibitoryactions of salbutamol occurred during long termadministration (Abel & Hollingsworth 1986).

In women suffering from severe :primary dys­menorrhoea, an intravenous infusion of salbuta­mol 10 1tg/min was capable of eliciting a large de­crease in uterine tonicity which was closelyassociated with pain relief (Lalos & Joelsson 1981).Salbutamol also caused an 18 to 50% reduction inuteroplacental blood flow following intravenousinfusion (16 1tg/min for 25 minutes) to women inthe last trimester of pregnancy, without uterine

Salbutamol: A Reappraisal

contractions (Lunell et al. 1982). Long term highdose oral therapy with salbutamol (4mg 5 times aday for 6 weeks) in women with past multiple preg­nancies had no effect on their current pregnancywith respect to duration of gestation and eventualbirthweight (Gummerus & Halonen 1987). How­ever , serum total oestriol concentration decreasedsignificantly in patients with premature labour fol­lowing intravenous salbutamol treatment (Hauk­kama & Gurrimerus 1982).

104 Metabolic Effects

The effects of salbutamol on certain indices ofbasal metabolism and on a number of hormoneshave been investigated in several studies. Of par­ticular interest are its effects on potassium, lipidand glucose metabolism.

1.4.1 Potassium MetabolismFollowing intravenous administration of sal­

butamol 120 ltg/kg/min for 30 minutes to healthysubjects , plasma potassium concentrations fell by0048 mmol/L, and by 0.93 mmol/L when adrena­line (0.6 ltg/kg/min for 30 minutes) was coadmin­istered with salbutamol (Whyte et al, 1987). Sim­ilar falls in plasma potassium levels (0.36 mmol/L) were seen in healthy volunteers receiving ne­bulised salbutamol 5mg (Rolf Smith et al. 1984).

Salbutamol 0.5mg intravenously was used totreat hyperkalaemia in 44 patients with chronicrenal failure , 20 of whom were receiving mainten­ance haemodialysis. Salbutamol caused a mean de­crease in plasma potassium of 0.9 mmol/L with in30 minutes. In the remaining 24 patients (who werenot receiving haemodialysis), mean plasma potas­sium concentrations fell from 7 mmol/L to 5.6, 5.6,6.0 and 6.2 mmol/L at 30, 60, 180 and 360 min­utes, respectively, after receivingsalbutamol (Mon­toliu et al. 1987). This suggests that salbutamol maybe effective in the treatment of hyperkalaemia inrenal failure. A reduction in plasma potassiumconcentrations was also observed in borderline hy­pertensive patients receiving salbutamol (Vincentet al. 1984). In addition, salbutamol 0.1 mg/kgorally attenuated the expected rise in plasma po-

85

tassium levels in patients receiving suxamethon­ium (Slater & McLaren 1987).

The mechanism by which salbutamol reducesplasma potassium concentrations is thought to berelated to stimulation of l3-adrenoceptors linked tomembrane-bound Na+/K+ATPase on skeletalmuscle , which causes an influx of potassium intocells, and not through 132-adrenoceptor-induced in­sulin release (Rolf Smith & Kendall 1984; Whyteet al. 1987).

1.4.2 Lipid EffectsFollowing intravenous infusion of salbutamol 6

ltg/min for 60 minutes to healthy volunteers, bloodlevels of non-esterified fatty acid (NEFA) increasedsignificantly from a baseline value of 556 ItEq/L toa peak of 1005 ItEq/L (Massi-Benedetti et al. 1982);this finding would suggest that salbutamol pos­sesses a specific lipolytic . action. Indeed, an in­crease of blood glycerol and NEFA occurred fol­lowing acute oral or intravenous administration ofsalbutamol to diabetic and non-diabetic pregnantwomen, and these effects were more pronouncedin the diabetic patients (Wager et al. 1982). Theinability to secrete insulin is thought to explain thisdifference, since insulin inhibits lipolysis (Wager etal. 1982). In an earlier study involving 23 pregnantwomen , increases in lipolysis were observed fol­lowing a single oral dose of salbutamol 4mg. How­ever, 13 of these women had been treated with oralsalbutamol 4mg 4 times a day for 12 to 33 dayspreceding the study and there was a less pro­nounced increase in lipolysis in this group, sug­gesting that tolerance may develop (Wager et al.1981). In 13 bronchial asthma patients receivingoral salbutamol 2mg 3 times daily for 3 months,plasma high density lipoprotein-cholesterol (HDL­cholesterol) and triglyceride concentrations re­mained constant during therapy (Lehtonen et al.1982). However, HDL-cholesterol increases of 6.9%were recorded in the plasma of 30 bronchiticpatients receiving oral salbutamol 8mg twice dailyfor 2 weeks, and it was suggested that dosage dif­ferences may explain these divergent results (Cha­zan et al. 1985).

86

1.4.3 Glucose and Insulin Effects,6-Receptors are involved in glycogenolysis and

insulin release, and salbutamol has been shown toincrease plasma concentrations of glucose and in­sulin in healthy volunteers (Rolf Smith & Kendall1984), .and in diabetic and non-diabetic patients(Wager et aJ. 1981, 1982).

Increases in both blood glucose and insulin wereobserved in diabetic and non-diabetic pregnantwomen following the acute intravenous infusionand oral administration of salbutamol, and theseeffects were more pronounced in the diabetics(Wager et aJ. 1982). The increase in glucose sug­gests the drug stimulates glycogenolysis in the liver,and rise in insulin indicates that salbutamol has adirect stimulatory effect on ,62-receptors in the in­sulin-secreting cells of the pancreas (Wager et aJ.1982). Moreover, a significant increase in immu­noreactive insulin (lRI) in 6 patients- 2 to 3 hoursafterreceiving salbutamol indicates that insulin-se­creting cells of the pancreas possess ,62-receptors(Stornello et al. 1983). Immunoreactive insulin re­sponses to salbutamol were also enhanced afterpreceding carbohydrate loads, indicating that glu­cose increased the sensitivity of the pancreas to ,62­adrenoceptor stimulation (Pihlajamaki & Huup­ponen 1982). Blood glucose concentrations and in­sulin secretion were both increased after intraven­ous administration of salbutamol 2 and 8 JLg/kg tohealthy volunteers following differing glucose loads.

The acute insul in-releasing capacity of salbuta­mol 2 JLg/kg was intensified and its blood glucoseelevating effect was diminished by preceding glu­cose loading. Raising the salbutamol dose from 2to 8 JLg/kg caused a 3.4-fold increase in insulin se­cretion and an even greater increase in blood glu­cose response (Huupponen & Pihlajamaki 1986).Such changes could well assume clinical signifi­cance in situations such as overdose and in preg­nant diabetic women.

1.4.4 Effects on Fetal MetabolismSince salbutamol undergoes maternofetal trans­

fer in experimental animals and humans (section2.2), it is likely to have an effect on fetal metab­olism. However, studies in this area are very lim-

Drugs 38 (1) 1989

ited. Long term administration of salbutamol topregnant rats was shown to increase fetal pan­creatic responsiveness to glucose, but no modifi­cation in fetal liver glycogen or birthweight couldbe demonstrated (Hauguel et aJ. 1982a,b). In preg­nant women treated with salbutamol 4mg 6 timesdaily for several weeks prior to parturition the drugdid not affect fetal endocrine thyroid status or cir­culating insulin. It did , however, significantly in­crease growth hormone levels, possibly due to di­rect stimulation of fetal pituitary production viaadrenergic receptors (Desranges et al. 1987).

1.5 Effects on the Central Nervous System

In various animal models used to assess centralnervous system activity salbutamol was found topossess antidepressant activity (Cowen et aJ. 1982;Erdo et aJ. 1982; Magilnicka 1982; Martin et aJ.1986). Furthermore, salbutamol has been reportedto be an efficacious antidepressant in humans (Le­crubier et al. 1980). It has been postulated that theseeffects are mediated through increased serotonergicsystem activity (Earley & Leonard 1983; Erdo etal. 1982; Sugrue 1982), although the clinical rele­vance of these findings is unclear.

Other reported central nervous system effects ofsalbutamol include inducing anorexia in rats ,through a mechanism involving ,6-adrenergic sitesin the brain (Borsini et aJ. 1985; Garattini & Sa­manin 1984), and raising vasopressin concentra­tions in the cerebrospinal fluid of dogs (Delbarreet aJ. 1982).

1.6 Inhibition of Allergic Responses

Like other ,6-adrenoceptor stimulants, salbuta­mol has demonstrated antiallergic activity both invitro and in vivo in humans.

1.6.1 In Vitro StudiesSalbutamol (0.03 to 3 JLmolfL) produces dose­

related inhibition of histamine release from pas­sively sensitised human lung fragments, with amaximum inhibition of 72.2% (Church & Young1983). Since the inhibition was totally prevented

Salbutamol: A Reappraisal

by propranolol it seems likely that this effect is me­diated via lung .B2-adrenoceptors. In similar studiessalbutamol inhibited anti-IgE-induced histaminerelease from human dispersed lung mast cells, withthe efficacy being inversely related to the concen­tration of anti-IgE used for challenge, and to thedegree of histamine release (Church & Hiroi 1987;Church et al. 1983). Salbutamol has little or no ef­fect on the inhibition of allergen-induced hist­amine release from leucocytes obtained from al­lergic patients (Mita & Shida 1983). However,pretreatment of lymphocytes from atopic asthmat­ics with salbutamol significantly inhibited the re­lease of high molecular weight neutrophil chemo­tactic activity (NCA), which has previously beendetected in the sera of patients suffering from awide variety of allergic diseases (Cundell & Davis1985). Salbutamol is only a weak inhibitor of anti­IgE-induced histamine release from human skinslices (Clegg et al. 1985).

1.6.2 Studies in Healthy VolunteersIntradermal application of 100/lgsalbutamol in­

hibited the histamine-induced cutaneous (weal) re­sponse in healthy volunteers. However, in healthyvolunteers with carbachol-induced bronchospasm,plasma histamine was significantly increased from0.25 mg/L to 0.43 mg/L after salbutamol inhala­tion 200/lg. Moreover, carbachol-induced bron­chospasm was simultaneously relieved from 51%to 103% of baseline specific airway conductance(Macquin et al. 1985).

1.6.3 Studies in Asthmatic PatientsSalbutamol is a potent inhibitor of mast cell

mediator release in asthmatic patients (Akam &Howarth 1984; Church et al. 1985; Howarth et al.1985; Sheinman et al. 1984) and in 1 study inhaledsalbutamol 200/lg was found to be superior to oralsalbutamol 8mg in this respect (Akam & Howarth1984). Pretreatment with inhaled salbutamol 200/lgsignificantly inhibited changes in FEV I , plasmahistamine and neutrophil chemotactic activity(NCA) in grass pollen-sensitive subjects who hadundergone bronchoprovocation (Church et al.1985), while in atopic asthmatics salbutamol 200/lg

87

prevented significant bronchoconstriction follow­ing allergen challenge (Howarth et al. 1985).

1.7 Effects on Ciliary Activity

Salbutamol has been shown to cause a small in­crease in mucin output in the lumen of cat tracheain situ (Peatfield & Richardson 1982). Further­more, salbutamol 10 /lg/kg administered intraven­ously increased ciliary beat frequency and muco­ciliary transport when given prophylactically toallergic sheep. In addition, it prevented antigen-in­duced falls in mucociliary transport by inhibitingmediator release, and reversed antigen-induceddepression of mucociliary transport (Abraham etal. 1984).

.B2-Adrenoceptor agonists have been shown tostimulate mucus secretion and mucociliary trans­port in normal subjects and patients with chronicbronchitis (Bateman et al. 1983). Mucociliaryclearance increased by up to 36% in chronic bron­chitis patients after adm inistration of nebulisedsalbutamol 0.5mg (Fazio & Lafortuna 1981), andin a similar study both healthy volunteers andpatients with chronic obstructive pulmonary dis­ease had increased mucociliary clearance rates fol­lowing nebulised salbutamol 0.5mg (Lafortuna &Fazio 1984). The increase was greater in the patients(33%)than in the volunteers (16%). Conversely, theadministration of salbutamol (4mg 3 times a dayfor 7 days) to patients with various respiratory dis­orders had little or no effect on mucociliary clear­ance function, however it was presumed that thisdosage was too low to elicit any effect (Isawa et al.1986).

1.8 Mechanism of Action

According to current theories, .B-receptor activ­ity is mediated by the production of cyclic aden­osine monophosphate (cAMP) as a 'second mes­senger'. The agonist (in this case salbutamol) bindsreversibly to the .B-adrenergic receptor, which is be­lieved to be adenyl cyclase or a closely associatedenzyme. When the ATP receptor of adenyl cyclaseis occupied simultaneously, ATP is converted to

88

cAMP, which is capable of triggering a sequence ofintracellular events that ultimately leads to a phys­iological effect (fig. 2). Most Ih-agonist broncho­dilators such as salbutamol appear to act directlyon receptors located on the surface of the airwaysmooth muscle cells, mast cells or other structures,rather than on presynaptic receptors (Ahrens &Smith 1984).

Radioligand binding studies have increased ourunderstanding of the mechanism by which {3­adrenoceptor agonists activate adenyl cyclase (Lef­kowitz et al. 1981). These have shown that the for­mation of a receptor high affinity state (HRX) isa functional intermediate in the mechanism ofhor­monal activation of adenyl cyclase; guanine nu­cleotides have an important role in that they causedestabilisation of the HRX, resulting in the stimu-

Drugs 38 (1) 1989

lation of adenyl cyclase. The intrinsic activity ofagonists appears to correlate with their ability tostabilise the intermediate.

It has been suggested that there are 3 molecularcomponents of the adenyl cyclase system: the re­ceptors (R), the nucleotide regulatory proteins (N),and the catalytic moiety (C), and that these existin both active and inactive states (Lefkowitz et al.1981).

The general model for {3-adrenergic agonist ac­tivation is shown in figure 3. The cycles of acti­vation/inactivation of the components are indi­cated as being interlocking, and the nucleotideregulatory proteins are the crucial elements cou­pling the receptor cycle to the cyclase cycle. In themembranes, at rest, each of the components is inits inactive state.

Phosphodiesterase -------4Insulinr::l Upids

L:JFig. 2. Diagrammatic representation of the sequence of intracellular events that lead to the physiological effects of a.B2-adrenoceptor agonist, like salbutamol:

Salbutamol: A Reappraisal

NGTP

S+R @ @GTP GOP

( ;-NGDP

SR ,

<D~ NGDP

Cinactive

e

89

,3-Adrenergicreceptor cycle

Nucleotide regulatoryproteincycle

Adenyl cyclasecatalytic moiety cycle

Fig. 3. Diagrammatic representation of the mechanism of action of the ,32-agonist salbutamol. The agonist (S; in this casesalbutamol) interacts with the receptor (R) and forms a binary complex SR (I); binding to the receptor promotes formationof a complex with the nucleotide regulatory proteins, SRN (2) and loss of tightly bound inhibitory GDP (3); GTP interactswith and stabilises SRN , freeing SR and NOTP (4) ; NoTP associates with the catal ytic moiety (C) to form activated adenylcyclase (5) which catal yses the conversion of ATP to cyclic AMP (6) ; NOTpe is hydrol ysed (7) and the components returnto the baseline state (after Lefkowitz et al. 1981).

2. Pharmacokinetic Studies

Pharmacokinetic information on salbutamol islimited because of the lack of readily availablemethods for measuring the drug and its metabo­lites. Those studies which have been reported gen­erally involved small numbers of volunteers andpatients to whom salbutamol would be expected tobe administered (i.e. asthmatics and pregnantwomen in preterm labour). Thus, further well-de­signed studies are needed to adequately describethe pharmacokinetic properties of the many form­ulations of salbutamol available, particularly thenewer controlled release preparations and the vari­ous formulat ions available for administration byinhalation techniques .

More detailed pharmacokinetic information maysoon become available since a number of sensitivehigh performance liquid chromatography (HPLC)assays have been reported recently (Hutchings etal. 1983; Morgan et al. 1986; Oosterhuis et al. 1984;Tan & Soldin 1984). In addition, the developmentof a chiral HPLC separation method for the opticalisomers of salbutamol will enable the stereoselec­tive disposition kinetics of the drug to be studied(Tan & Soldin 1987).

2.1 Absorption

In healthy volunteers salbutamol is well ab­sorbed following oral administration, with peakplasma concentrations occurring within 1 to 4 hours(tmax). Individual variations in maximum plasmaconcentrations occur, as seen by individual peakplasma concentrations of 7.2 to 18.1 /oLg/L after anoral dose of 4mg (Jonkman et al. 1986; Macono­chie & Fowler 1983; Morgan et al. 1986; Powell etal. 1985; Sykes et al. 1987). Despite the fact thatsalbutamol is well absorbed, its systemic bioavail­ability is only 50%, due to extensive presystemicmetabolism in the intestinal wall (Morgan et al.1986).

Steady-state plasma concentrations of salbuta­mol are generally in good agreement with predictedvalues, and were attained after 3 days' administra­tion of oral salbutamol 4mg 4 times a day to 12healthy volunteers (Powell et al. 1986). However,after intravenous salbutamol (400/oLg loading dose,with a maintenance infusion of 10 /oLg/min for 2hours) steady-state concentrations were notachieved by the end of the 2-hour infusion (Mor­gan et al. 1986). These data support the theory ofAhrens and Smith (1984) that salbutamol has aprolonged distribution phase lasting longer than 2hours.

90

No recent studies on salbutamol administrationby inhalation appear to have been published; how­ever, earlier research demonstrated that after aero­sol administration by metered dose inhaler the ma­jority of drug is swallowed and handled orally, theresultant plasma concentrations being an order ofmagnitude smaller than those produced by usualoral doses (Walker et aJ. 1972). The small fractionthat is delivered to the lung [usually less than 10%(Dolvich et aJ. 1981)] rapidly appears in the cir­culation as free unmetabolised drug (Shenfield etaJ. 1976).

2.2 Distribution

The kinetic model that best describes the phar­macokinetics of salbutamol is a 2-compartmentopen model with first-order absorption kinetics(Powell et aJ. 1986). In humans, salbutamol is rap­idly absorbed and distributed into tissues. Follow­ing an intravenous infusion of salbutamol 10 /lg/min for 2 hours an apparent volume of distribu­tion (Vd) of 156L was documented, and this is in­dicative of extensive extravascular uptake (Morganet aJ. 1986).

Studies in rats and dogs have shown that 3H_salbutamol is rapidly cleared from all tissues, andthe liver and kidney were the only organs in whichsmall amounts of radioactivity were detected 24hours after oral administration of the drug (Martinet aJ. 1971).Placental transfer of 3H-salbutamol oc­curs in pregnant rats, with 10%of maternal plasmasalbutamol being recovered in fetal plasma (Gar­dey-Levassort et aJ. 1982). In vitro studies with iso­lated human placental lobes also showed that 12%of salbutamol underwent placental transfer frommaternal to fetal plasma (Nandakumaran et aJ.1981). Direct evidence of maternofetal transfer ofsalbutamol has also been demonstrated in humans(Dellenbach et aJ. 1977). After intravenous admin­istrat ion of salbutamol 10 mg/kg to rats approxi­mately 5% of the plasma salbutamol concentrationpenetrated the blood-brain barrier, supporting thetheory that stimulation ofcentral ~-adrenergic sitesmay be responsible for some of the drug's phar­macological effects (Caccia & Fong 1983). High

Drugs 38 (1) 1989

cardiac muscle concentrations have been reportedin dogs following intravenous administration ofsalbutamol 50 mg/kg, and this may help explain,in some part, the drug's effect on heart rate (Sauxet aJ. 1986).

Ultracentrifugation studies using human plasmahave shown that only 8% and 7% of salbutamol isbound to plasma proteins at concentrations of 50and 200 /lg/L,·respectively (Morgan et aJ. 1986).However, using an equilibrium dialysis technique,Nandakumaran et aJ. (1981) reported that at a con­centration of 2 mg/L the extent of salbutamolbinding to plasma proteins was approximately 64%.The blood/plasma concentration ratio for salbu­tamol was found to be approximately I (Morganet aJ. 1986).

2.3 Metabolism and Elimination

In humans salbutamol and its metabolites arerapidly excreted in urine and faeces. After oral in­halation of single doses of 3H-salbutamol (40 to100jlg) in patients with asthma, approximately 70%of the dose was excreted in urine as unchanged drugand metabolites within 24 hours, and 80 to 100%within 72 hours ; about 30% of the dose was ex­creted in urine as unchanged drug in 24 hours , andup to 12% of an inhaled dose may be excreted infaeces (Evans et al. 1973). Following oral admin­istration of salbutamol 4mg to volunteers, about80% of the dose was excreted in urine, with ap­proximately 30% being unchanged drug (Morganet aJ. 1986). The similarity between oral and in­haled excretion patterns of salbutamol suggests thatthe majority of an inhaled dose is swallowed. Fol­lowing intravenous infusion of salbutamol 10 /lg/min for 2 hours to volunteers , over 75%of the dosewas recovered in urine within 24 hours, with ap­proximately 65% being unchanged drug and 10%metabolite (Morgan et aJ. 1986). The different ex­cretion patterns seen following oral and intraven­ous administration is a result of presystemic me­tabolism in the gastrointestinal mucosa (Morgan etal. 1986).

Salbutamol is almost exclusively metabolised byconjugation to a 4'-O-sulphate ester in the intes-

Salbutamol: A Reappraisal

tinal wall and liver (Ahrens & Smith 1984; Evanset al. 1973; Morgan et al. 1986). A second minormetabolite has been reported in the urine of asth­matic patients receiving inhaled salbutamol; how­ever, it represented only 4% of the dose and wasnot chemically identified (Lin et al. 1972). Plasmaconcentrations of the sulphate conjugate are ap­proximately 5 times those of salbutamol 1 to 5hours following oral and inhaled doses (Evans etal. 1973; Morgan et al. 1986; Walker et al. 1972);this metabolite is virtually undetectable followingintravenous administration (Morgan et al. 1986).The 4'-O-sulphate metabolite possesses little or no~-adrenergic activity (Evans et al. 1973).

The mean total plasma clearance of salbutamolfollowing intravenous administration (10 ttg/minfor 2 hours) was 28.8 L'h, with the major route ofelimination being via the kidneys (Morgan et al.1986). In fact, the renal clearance of salbutamolfollowing both oral and intravenous administra­tion has been shown to be similar (16.3 and 17.5Llh, respectively) and significantly greater thancreatinine clearance (7.1 L/h). This suggests thatactive tubular secretion plays a major role in therenal excretion of salbutamol (Morgan et al. 1986).The renal clearance of the 4'-O-sulphate metabolitewas much less (5.91 Lzh) than that of salbutamol,and could be taken to indicate that it is freely fil­tered at the glomerulus, with no active secretionoccurring (Morgan et al. 1986).

2.3.1 Elimination Half-LifeIn healthy subjects the elimination half-life (t'l2/3)

of salbutamol after single oral doses of 4mg was2.7 to 5.5 hours (Jonkman et al. 1986; Powell etal. 1985). However, volunteers receiving salbuta­mol 4mg 4 times a day for 5 days had a slightlyincreased elimination half-life of 6.5 hours. Thehalf-life of salbutamol administered intravenouslyto healthy volunteers was 3.8 hours following aninfusion of 10 ttg/min for 2 hours (Morgan et al.1986) and 2.4 to 3.0 hours following an injectionof 8 ttg/kg (Soininen et al. 1983). In this latter studythe elimination half-life calculated from urinarydata was 3.4 to 4.2 hours. Similarly, after single­dose inhalation of salbutamol 84 and 200ttg in

91

Table II. Pharmacokinetics of salbutamol after intravenous and

oral administration in premature labour patients and healthy

volunteers (after Hutchings et al. 1987)

Kinetic parameter Healthy Premature p valuevolunteers labour

Systemic availability (%) 50 43 < 0.05% dose excreted 31.9 18.7 < 0.05

unchanged in urine

% dose excreted as 48.2 34.6 NSsulphate conjugate in

urine

AUCeon{AUCsaia 5.2 4.0 0.058Total clearance (L{h) 28.8 30.06 NSSalbutamol renal clearance 16.98 12.83 < 0.05

(L{h)

Salbutamol conjugate renal 5.91 5.83 NS

clearance (L{h)Creatinine clearance 118 98.7 < 0.05

(ml{min)

a AUC of the sulphate conjugate divided by the AUC of sal-butamol during oral administration.

Abbreviation: NS =non-significant difference

healthy volunteers the half-life of unchanged drugwas 3.8 hours based on urinary excretion data (Linet al. 1972). The elimination rate of the 4'-O-sul­phate metabolite was similar to that of unchangedsalbutamol following oral administration of thedrug to healthy volunteers, indicating that the ki­netics of elimination of the sulphate metabolite areformation rate limited.

2.4 Pharmacokinetics of Salbutamol inPregnancy

The pharmacokinetics of salbutamol and its sul­phate conjugate were examined following initialintravenous administration and longer term oralmaintenance therapy in 9 patients receiving thedrug for the prevention of preterm labour (Hutch­ings et al. 1987). Overall there were only minordifferences in salbutamol pharmacokinetics whencompared with a group of healthy men and non­pregnant women (table II; Morgan et al. 1986). Thetotal clearance of salbutamol and formation andelimination of the sulphate conjugate were similar.

92

The systemic availability, urinary recovery of un­changed salbutamol and area under the plasmaconcentration curve were all slightly lower (10 to20%) in the patient group than in the healthyvolunteer groups. However, renal salbutamolclearance was significantly lower in the prematurelabour patients.

2.5 Controlled Release Preparations

In a randomised crossover study, Powell et al.(1987) compared steady-state plasma concentra­tions following repeated administration of a 4mgcontrolled release tablet (twice daily) and a 2mgconventional tablet (4 times daily) for 5 consecu­tive days in 12 healthy volunteers. The data showedthat the controlled release tablet was bioequivalentto the more conventional regimen. Mean steady­state plasma concentrations for both 'controlled re­lease and conventional tablets were similar, andthere were no significant differences in area underthe plasma concentration-time curves (AVC) andmaximum (Cmax)or minimum (Cmin) plasma con­centrations. A diurnal fluctuation was observed inCmax values for the controlled release tablet, sug­gesting the rate of absorption of salbutamol for thisformulation is somewhat different during the nightthan during the day.

Comparison of AVC for normal (4mg) and con­trolled release salbutamol preparations (8mg) inhealthy volunteers and patients with reversible ob­structive airways disease are similar, although peakconcentrations tend to be lower (12.2 to 14.3 J,lg/L) and take longer to be attained (4.4 to 6 hours)with controlled release preparations. However, thedrug profile in the controlled release groups wassmooth in comparison to peaks and troughs whichoccurred with normal tablets. This should result infewer adverse effects and a longer therapeutic effect(Maconochie & Fowler 1983; Milroy et al. 1988;Sykes et al. 1987).

In a recent study Lepworth et al. (1988) com­pared single-dose and steady-state pharmacokin­etics of salbutamol 4 and 8mg controlled releasepreparations given twice daily to patients withasthma. After single doses mean Cmax was 4.6 and

Drugs 38 (1) 1989

9.5 J,lg/L, respectively. At steady-state , mean Cmaxvalues were 8.2 and 16.1 J,lg/L, respectively. Me­dian tmax values were 5 and 4 hours for 4 and 8mg,respectively.

3. Therapeutic Trials in RespiratoryDiseases

For almost 20 years salbutamol has been widelyused, and the drug is currently well established inthe management of reversible obstructive airwaysdisease. However, during this time a number ofselective bronchodilator drugs have been devel­oped which may offer suitable alternatives to sal­butamol. Therefore, it is important to reassess theefficacy of salbutamol relative to these drugs in thetreatment of the disease.

Reversible obstructive airways disease encom­passes a wide spectrum of diseases ranging in se­verity from mild forms of asthma to chronic ob­structive lung disease. The clinical features of thesediseases often overlap and hence diagnoses such as'chronic bronchitis with asthmatic features' and'chronic bronchitis and emphysema' are frequentlyused. Correspondingly there is often an overlap oftreatments. However, it is possible to assess theefficacy of salbutamol in the treatment of a num­ber of clinically definable disease states, includingsevere acute asthma (section 3.3), childhood asthma(section 3.4) and exercise-induced asthma (section3.5). Moreover, an appraisal of the efficacy of sal­butamol in the treatment of reversible obstructiveairways disease is given (section 3.2), which for thepurpose of this review is taken to include mild tomoderate and chronic asthma and all forms of ob­structive lung disease which have a reversible com­ponent.

Most studies with salbutamol have made rea­sonable attempts to minimise the effects of naturalvariability of reversible obstructive airways dis­ease, and adopted the usual accepted measures suchas assessments made at the same time each day,frequent lung function measurements, matchedtreatment groups, randomisation, lengthy run-inperiods, etc.

Entry criteria usually required baseline (un-

Salbutamol: A Reappraisal

treated) forced expiratory volume in 1 second(FEY1) to be less than 80% of predicted normalvalues. In addition, most patients had to show anincrease of at least 15% in FEY1 following a testdose of inhaled t32-agonist. Many studies also re­ported that patients were taken off other broncho­dilators at least 12 hours before testing respiratoryfunction. Measurement of specific airways resist­ance (SGaw) by whole body plethysmography is thepreferred method for evaluating bronchodilation,since it is independent of patient cooperation.However, spirometric assessment of airway func­tion is easier to perform, and consequently has beenused in most of the reported studies. As would beexpected of a drug that brings about rapid relief ofbronchoconstriction, most studies have been singledose or short term, though a few authors have re­ported longer term studies.

3.1 Influence of Formulation on the Efficacyof Salbutamol

The efficacy and relative selectivity ofbroncho­dilator drugs such as salbutamol is largely depend­ent on its mode of delivery, with the route ofadministration being an important determinant ofthe balance of beneficial and adverse effects (Shen­field 1982; Tattersfield 1984). Salbutamol can beadministered by inhalation, orally, or parenterally,and consequently its clinical efficacy has been as­sessed in patients with reversible airflow obstruc­tion of multifactorial aetiology following admin­istration by these routes. Most of the studiesundertaken have been single dose and compare dif­ferent formulations of salbutamol (e.g. oral versusinhaled), although a few long term comparative andnon-comparative studies have been reported .

3.1.1 Inhaled SalbutamolThe advantages of inhalation in terms of its

speed of onset, low incidence of side effects andconvenience of administration make inhaled sal­butamol a first-line treatment in the majority ofpatients with reversible obstructive airways dis­ease. Salbutamol is available for inhalation in 3formulations: aerosol, dry powder, and solution for

93

nebulisation. In view of the much higher doses (~

2.5mg) used with the latter technique, its efficacyis reviewed separately (see section 3.1.2).

The majority of patients requiring inhaled sal­butamol therapy administer the drug from a pres­surised aerosol. A substantial number of patientsare unable to coordinate the use of a pressurisedaerosol, but they can usually be treated successfullywith the dry powder formulation . Importantly, nostatistically significant difference was found be­tween the bronchodilator effect of single doses ofinhaled salbutamol when administered as a drypowder or from a pressurised aerosol (Anandajeya& Sivakumaran 1984; Bronsky et al. 1987; Latimeret al. 1982; Svedmyr et al. 1982).

Latimer et al. (1982) reported that the broncho­dilating effect of pressurised aerosol (200jlg) anddry powder salbutamol (200 and 400jlg) were al­most identical, with both formulations eliciting sig­nificantly greater increases (p < 0.001) in FEY1 andFVC than placebo. Peak bronchodilation occurredwithin 15 minutes and was maintained for 2 hours,remaining above baseline values for 5 hours. An­andajeva and Sivakumaran (1984) also showed thatsalbutamol 400jlg dry powder and pressurisedaerosol 200jlg have equivalent bronchodilatory ef­fects. In a cumulative dose-response study Sved­myr et al. (1982) reported that 5 doses of pressur­ised aerosol salbutamol (0.1 to 2.4mg) and 5 dosesas a dry powder (0.2 to 4.8mg) had almost identicalFEY1 dose-response curves. Salbutamol dry pow­der 400jlg and salbutamol 200jlg from a pressur­ised aerosol were equally effective in relieving acutemetacholine-induced bronchial obstruction inasthmatic patients (Lahdensuo et al. 1983; Sovi­jarvi et al. 1982).

In a multicentre randomised double-blind pla­cebo-controlled study, Bronsky et al. (1987) com­pared the efficacy and safety of aerosolised salbu­tamol 180jlg 4 times daily with the dry powderformulation 200jlg 4 times daily in 231 patientswith chronic reversible obstructive airways diseasefor a period of 12 weeks. No statistically significantdifferences were found between the 2 formulationswith respect to pulmonary function and length of

94

time mean FEV1 remained ~ 15% above baselinevalues.

Several recent studies have compared the effi­cacy and safety of inhaled salbutamol administeredby the recently developed multi-dose dry powderinhaler 'Diskhaler' with the more established aero­solised and dry powder delivery systems of the drug(Berg et al. 1988; Pover et al. 1988; Svendsen et al.1988). In a single-dose study involving 42 asth­matic patients it was shown that the bronchodi­latory response to aerosolised salbutamol 200~g

delivered from a metered dose inhaler was almostidentical to that observed when salbutamol 400~gwas inhaled from the 'Diskhaler'system (Pover etal. 1988). Furthermore, long term studies (up to 3weeks) in children and adults with reversible ob­structive airways disease have demonstrated thatdry powder salbutamol 200 or 400~g administered4 times dail y from the 'Diskhaler' inhaler is clinic­ally equivalent to the same dose administered fromthe 'Rotahaler' inhaler (Berg et al. 1988; Svendsenet al. 1988), and the majority of patients expresseda preference -for the 'Diskhaler' system. Thus the'Diskhaler' device should provide a useful additionto the current range of delivery systems available.

It is apparent from these studies that salbuta­mol 200~g by pressurised aerosol inhalation and400~g by dry powder inhalation have equivalentbronchodilatory effects.

3.1.2 Nebulised SalbutamolThe administration of a respirator solution of

salbutamol via a nebuliser constitutes the inhala­tion of a wet aerosol. However, much higher dosesof salbutamol are used with nebulisation than withthe 2 previously described inhalation techniques(see section 3.1.1).

Salbutamol solution is usually administered bynebuliser at a dosage of 5mg. However, followinga dose-ranging study in 12 asthmatic patients, WaI­ters 'et al. (1981) suggested 3mg of salbutamol ne­buliser solution may be an optimal dose for bron­chodilation. Patients received increasing doses ofsalbutamol1.5, 3.0, 7.5mg and placebo twice dailyfor 4 days in a double-blind clinical trial , and therewas a significant (p '< 0.0 I) dose-related response

Drugs 38 (1) 1989

for FEV ( and PEF versus baseline. However, therewas also a significant dose-related response in sideeffects (p < 0.01).

The feasibility of long term treatment with ne­bulised salbutamol has been demonstrated in astudy involving 27 asthmatics who received ne­bulised salbutamol 2.5mg twice daily for a meanperiod of 2.7 years. Although no spirometric testswere performed during the study many of thepatients experienced subjective relief, with 6 of thepatients being taken off concomitant oral cortico­steroid treatment (Boe 1984).

3.1.3 Oral SalbutamolIn 124 asthmatic patients who received either 4

or 6mg single oral doses of salbutamol, a rapid andsignificant improvement in FEV ( was observedwhen compared with placebo. The improvement,which peaked at 2 hours (p < 0.0 I), continued forup to 8 hours (p < 0.01) with the 4mg dose, andup to 10 hours (p < 0.01) with the 6mg dose.Changes with respect to forced vital capacity (FVC)and midflow forced expiratory flow rate (FEF25_75%) mirrored those reported for FEV i- However,these improvements were associated with a sig­nificant increase (p < 0.01) in side effects whencompared with placebo (Rosen et al. 1986).

A number of studies have demonstrated the ef­fectiveness of controlled release salbutamol tabletsin patients with reversible obstructive airways dis­ease. In double-blind trials of 2 to i 12 weeks dur­ation involving 355 patients with asthma, bron­chitis or emphysema, twice daily administration ofcontrolled release salbutamol 8mg and a standardtablet of salbutamol 4mg 4 times daily producedsimilar improvements in lung function as reflectedby changes in FEV1, FVC, VC or PEF (Dahl 1988;Nielsen et al. 1988). However, in a 2~week placebo­controlled double-blind crossover study involving20 patients with reversible airways obstruction,controlled release salbutamol 8mg twice daily wasclinically superior to standard salbutamol 4mg 4times daily. During treatment with the controlledrelease tablets, morning PEF was significantlyhigher (p < 0.05), wheeze was significantly lower(p < 0.05) and there was a lesser need for inhaled

Salbutamol: A Reappraisal

bronchodilators for breakthrough asthma attacks(Maesen & Smeets 1986a). Moreover, in patientswith symptoms of nocturnal asthma , a single oralnight-time dose of controlled release salbutamol8mg has been shown to significantly improvemorning PEF (p < 0.001), symptoms of wheeze (p< 0.05) and shortness of breath on waking (p <0.0 I) [Moore-Gillon 1988].

In double-blind parallel group studies of 6 weeksduration involving children (n = 237) and adults(n = 197) with asthma, twice daily administrationof controlled release salbutamol 4mg and a stand­ard tablet of salbutamol 2mg 4 times daily pro­duced similar improvements in lung function(Pedersen et al. 1988;Weller 1988). However, whilstboth treatments proved safe and effective in thechildren (Weller 1988), neither treatment regimenswere totally effective in the adult asthmatics as fre­quent , additional inhaled medication was requiredto maintain control of their symptoms. Conse­quently a higher oral dose could be required in thesepatients (Pedersen et al. 1988).

3.1.4 Parenteral SalbutamolParenteral salbutamol, particularly when ad­

ministered intravenously, is indicated in the treat­ment of severe acute asthma (see section 3.3); how­ever, it is often associated with dose-dependenttachycardia.

No statistically significantdifferenceswere foundbetween the bronchodilator effect of single 0.4 /J-g/kg intravenous and intramuscular doses of salbu­tamol in asthmatic patients. Administration by bothroutes resulted in a significant increase in FEV, 15minutes after injection (p < 0.05) that was sus­tained for up to 3 hours. However, parenteraladministration was associated with significant (p< 0.0I) increases and decreases in heart rate anddiastolic blood pressure (Rebuck & Contreras 1982).

3.1.5 Inhaled Versus Nebulised SalbutamolSalbutamol 4.8mg administered by aerosolisa­

tion over a 12-minute period was as effective interms of improvement in FEV, and FVC as thesame dose given by intermittent positive pressure

95

breathing nebulisation in a group of chronic asth­matic patients (Anderson et al. 1982).

Harrison and Pierce (1983) compared the bron­chodilator responses to cumulative doses of in­haled salbutamol aerosol 800/J-g (8 X 100/J-g) andnebulised salbutamol IOmg (4 X 2.5mg) in 10 asth­matic patients with chronic airways obstruction.Both the inhaled and the nebulised modes ofadministration produced increasing and equivalentbronchodilation over the dosage ranges, with nosignificant difference in the maximal response inFEV" FVC, PEF, Vmax 50% or Vmax 75%. In alonger term double-blind crossover study, 19patients with chronic airflow limitation completed8 weeks' treatment with nebulised salbutamol2.5mg 4 times daily and with inhaled salbutamol200/J-g 4 times daily. No significant difference be­tween the 2 delivery methods was observed withrespect to daily PEF, severity of symptoms, extrabronchodilator usage or side effects (Jenkins et al.1987).

3.1.6 Inhaled Versus Oral SalbutamolLouridas et al. (1983) reported that the bron­

chodilator response of inhaled salbutamol Img(200/J-g administered every 20 minutes) was sig­nificantly greater than a single oral 2mg dose ofsalbutamol in 10 patients with bronchial asthma.Moreover a combined regimen of both oral andinhaled preparations was additive in the samepatients. FEV, increased rapidly and markedly onboth the combined and inhaled regimens, and after120 minutes had increased by 23.5% and 22.5%,respectively. These increases were significantlygreater (p < 0.02) than observed with oral treat­ment (9.25%). Similar changes in FVC were alsoobserved.

Combined treatment with single doses of oral(4mg) and inhaled (400/J-g) salbutamol was superiorto either treatment administered alone in 18 asth­matic patients. The combined treatment had a rapidonset of effect, due to the inhaled component, anda sustained period of action, reflecting the sloweraspects of the oral component (fig. 4). Mean per­centage increases in PEFR following the combined,

96 Drugs 38 (1) 1989

Fig. 4. Mean percentage improvement in peak expiratory flowfrom baseline values in 18 asthmatic patients after oraladministration of salbutamol 4mg (e), inha led salbutamol400l'g (L'.)and a combination of inhaled 400l'g and oral 4mgsalbutamol (_) [after Grimwood et al. 1983J.

inhaled and oral treatments were 49%, 26.2% and19.5%, respectively.

Although all 3 treatments were well tolerated,the combined and oral treatments produced slightbut significant increases in heart rate (p < 0.01)when compared with inhalation alone (Grimwoodet al. 1983).

It 80Q.

.6EQ) 60EQ)e.g- 40

~:2 20

1 2Time (h)

3 4 5 6

3.2.2 Comparisons with Other !J2-AgonistsThere have been a large number of studies in

which single doses of salbutamol have been com­pared with different ~2-adrenoceptor agonist drugsin patients with reversible obstructive airways dis­ease. In general, there are no major clinical differ­ences between these agents (table III), despite thevariable nature of the disease state.

BitolterolStudies comparing inhaled salbutamol 180J.{g and

inhaled bitolterol approximately l.lmg in patientswith asthma have shown that both drugs produceeffective bronchodilation within 5 minutes with amaximum effect at 30 to 60 minutes. Although themean percentage increase in FEVI, FVC andFEF25-75%over baseline was higher with bitolterol,only mean improvement in FEV1 at 5 to 8 hoursafter medication demonstrated statistically signifi­cant differences (p < 0.05) between treatments. Thissuggests that bitolterol has a longer duration of ac­tion than salbutamol. However, it should be notedthat in these studies equipotent doses of the drugswere not used which accounts for the greater dur­ation of action of bitolterol (Orgel et al. 1985; Tin­kelman et al. 1983).

3.2 Use in Reversible ObstructiveAirways Disease

3.2.1 Comparisons with PlaceboMany of the clinical trials assessing the efficacy

of various salbutamol formulations have been per­formed in patients with reversibJe obstructive air­ways disease, and many of these studies utilised aplacebo as part of the study design (see section 3.1).In such studies salbutamol produced significantlysuperior bronchodilation compared with placebo.Similarly, most clinical trials comparing salbuta­mol with other bronchodilator .drugs in patientswith reversible obstructive airways disease alsoutilised placebo administration as part of the studydesign (see tables III and IV), and in such studiesboth salbutamol and comparator drugs were su­perior to placebo.

BroxaterolIn several double-blind crossover studies, single

oral doses ofsalbutamol4mg and broxaterol 0.5mgboth improved lung function in patients with re­versible bronchial obstruction. The 2 drugs sig­nificantly increased FEV1 (p < 0.05) for 5 hourscompared with baseline values and for 2 hourscompared with placebo values (Blasi & Pezza 1985;Perruchoud et al. 1987). In addition, Casali et al.(1988) compared the bronchodilating effects of in­haled broxaterol 200 and 400J.{g with inhaled sal­butamol 200J.{g in patients with bronchial asthmaand chronic obstructive bronchitis. There were nosignificant differences between the effects of sal­butamol and broxaterol 400J.{g on FEVI, FVC,maximum mid-expiratory flow (MMEF) and max­imal expiratory flow rate at 25% of vital capacity(MEF25). However, salbutamol was significantlysuperior to broxaterol 200J.{g on FEV1 at 7.5 and

Salbut amol: A Reappraisal 97

Table III. Summary of some selected single-dose comparat ive trials of salbutamol (S) and other J32-adrenoceptor agonists in patients

with reversible obstructive airways disease

Reference No. of Study Dosage, route Results (pulmonary function)a Adverse Overallpts design effectsb efficacy

FEV1 FVC time to duration ofmax. actioneffect

Comparison with bitolterol (B)Orgel et al. 120 r, db, pi S 180"g Inh S=oB S=oB S=oB B >S S=oB S=oB(1985) B 1.11mg Inh

Comparisons with broxaterol (Bx)Casali et al. 12 r, db, co S 200"g Inh S =0 Bx S =0 Bx S =0 Bx S =0 Bx S =0 Bx S =0 Bx(1988) Bx 200, 400"g

InhPerruchoud et 18 r, db, co, S 4mg PO S =0 Bx S =0 Bx S =0 Bx S =0 Bx S =0 Bx S =0 Bxal. (1987) pc Bx 0.5mg PO

Comparison with clenbuterol (C)Papiris et at. 12 sb, co, pc S 1mg Neb S=oC S=oC S=oC S=oC(1986) C 30"g Neb

Comparison with fenoterol (F)Maesen et al. 20 r, db, co, S 400"g Inh S=oF S=oF S >F F >S S=oF S=oF(1984) pc F 200"g Inh

Compar isons with isoetharine (Ie)Berezuk et al. 10 r, db, co, S 280" g Inh S > Ie S > Ie S =0 Ie S > Ie S =0 Ie S > Ie(1983) pc Ie 680"g InhStorms et al. 121 r, sb S 2.5mg Neb S > Ie S =0 Ie S > Ie Ie > S S > Ie(1986) Ie 2.5mg Neb

Comparisons with isoprenaline (Is) [ isoproterenol]Bedell & 15 r, db, co S 170"g Inh S =0 Is S =0 Is S =0 Is S > Is Is > S S > IsRichardson Is 150"g Inh(1981)Light et al. 130 db S 2.5mg Neb S =0 Is S =0 Is S > Is Is > S S > Is(1984) Is 2.5mg Neb

Comparisons with orciprenaline (0)Ahrens et al. 13 r, db, co, S 90, 180"g Inh S=oO S=oO S=oO S=oO 8=00(1987) pc 01 .3,2.6mg

InhHabib et al. 20 r, db, pi 8 5mg Neb 8=00 8=00 8=00 S=oO 8=00(1987) o 15mg Neb

Comparisons with procaterol (Pc)Crowe et al. 24 r, db, co S 5mg PO 8 =0 Pc 8 =0 Pc 8 =0 Pc 8 =0 Pc 8 =0 Pc 8 =0 Pc(1985) Pc 50 100"g POMorin et al. 18 r, db, co 8 180"g Inh 8 =0 Pc 8 =0 Pc S =0 Pc 8 =0 Pc 8 =0 Pc(1987) Pc 20"g Inh

Compar isons with terbutaline (T)Sahay et al. 20 r, db, co 8 250"g IV 8=oT 8=oT 8=oT 8=oT 8 ~T 8=oT(1984) T 500"g IVWolfe et al. 20 r, db, co S 4mg PO S=oT 8=oT 8=oT 8=oT T >S 8=oT(1985) T 5mg PO

a All drugs generally produced statistically significant changes compared with baseline values. However, statistically significant

differences between S and comparator drugs were rare. =0 indicates that 8 was as effect ive as the comparator drug; 8 ~ indicatessalbutamol tended to be superior to the comparator drug; 8 > indicates salbutamol was superior to the comparator drug.

b Adverse effects were mild for all drugs; =0 indicates that 2 drugs produced equivalent adverse effects; X ~ indicates that drug

X tended to produce more adverse effects ; X > indicates that drug X produced significantly more adverse effects .

Abbreviations: r = randomised; db = double-blind ; co = crossover ; pc = placebo-cont rolled; sb = single-blind; pi = parallel;

Inh = inhaled; PO = oral ; Neb = nebulised; IV = intravenous.

98 Drugs 38 (1) 1989

Table IV. 8ummary of some selected single-dose comparative trials of salbutamol (8) and some.anticholinergic drugs in patients

with reversible obstruct ive airways disease

Reference No. of Study Dosage. route Results (pulmonary function)8 Overall

pts designFEV, FVC time to max. duration of

efficacy

effect action

Comparison with atropine (A)

Molho et al. 14 r, sb, co 8 0.045 mg/kg 8==A 8==A 8==A

(1987) Neb

A 0.035 mg/kgNeb

Comparison with atropine methonitrate (An)

Maesen & 16 r, db, co, 8 0.1mg Inh 8 + An " 8 > 8 + An == 8==8+An 8 == 8 + 8==8+An

8meets (1985) pc An 1mg Inh An 8 > An > An An > An > An8 + An Inh

Comparison with ipratropium bromide (Ip)

Chan et al. 20 r, co, pc 8 5mg Neb 8 + Ip > 8 sss 8 + Ip > 8 + Ip sss 8 8 + Ip > 8 + Ip > 8 ==(1984) Ip 0.5mg Neb Ip Ip > 8 == Ip 8 == Ip Ip

8 + Ip Neb

Comparison with ipratropium bromide/fenoterol combination (Ip + F)

Crane (1986) 10 r, db, co, 8 200/lg Inh Ip + F > 8

pc Ip 80/19 + F200/lg Inh

8 == Ip + 8 == Ip + F Ip + F > 8 Ip + F > 8F

Comparison with oxlfrcptum (Ox)

Tukiainen & 12 r, co, pc8alorinne

(1985)

8 200, 400/lg InhOx 200/lg Inh

8 200/lg + Ox2001'91nh

8400>8+Ox > 8200 >Ox

8400>8+Ox > 8200> Ox

8400>8+Ox > 8200>Ox

a All drugs generally produced statistically significant changes compared with baseline values. However, statistically significantdifferences between 8 and comparator drug were rare. == indicates that 8 was as effective as the comparator drug; 8 ., indicatessalbutamol tended to be superior to the comparator drug; 8 > indicates salbutamol was superior to the comparator drug.

Abbreviations : r = randomised; db = double-blind; co = crossover ; pc = placebo-controlled ; sb = single-blind; Inh = inhaled;Neb = nebulised.

15 minutes (p < 0.05) postadministration, and onFVC, MMEF and MEF25 (p < 0.05) also 15 min­utes postadministration.

ClenbuterolIn a single-blind placebo-controlled trial in 12

patients with chronic obstructive pulmonary dis­ease, single nebulised solutions of salbutamol Imgand clenbuterol 30jlg produced similar improve­ments in FEVI and FVC. However, salbutamol hada greater effect on maximal expiratory flowsVmax 50% (p < 0.01) and Vmax 75%(p < 0.05) [Pa­piris et al. 1986]. Similarly, in multiple-dose stud-

ies comparing oral salbutamol 2 or 4mg 3 timesdaily with oral clenbuterol 20 or 40jlg twice dailyfor periods of up to 2 weeks, there were no sig­nificant differences between the 2 drugs with re­gard to daily respiratory function indices, or inpatient preference. Interestingly, doubling the doseofeither drug did not result in any significant extrabenefit (Blom-Bulow et al. 1985; Jaffe & Grimshaw1983).

FenoterolIn several double-blind crossover studies in

patients with reversible obstructive airways dis­ease, single doses of inhaled salbutamol (200 to

Salbutamol: A Reappraisal

400~g) and fenoterol (200 to 320~g) produced ef­fective and equivalent bronchodilation. Statisti­cally significant differences were found in a few lungfunction parameters, and these tended to indicatethat fenoterol had a slightly longer duration of ac­tion, although salbutamol appears to have a morerapid onset of effect. Overall the differences be­tween the 2 drugs did not appear to be clinicallyrelevant (Hey & Gillies 1985; Konig et aL 1985;Maesen et al. 1984).Similar findings have been ob­served when salbutamol and fenoterol have beenadministered by nebulisation. Lahdensuo (1984)reported a study in which patients with asthma orchronic bronchitis received nebulised solutions offenoterol 0.5mg and salbutamol 5mg in a double­blind clinical trial. Both drugs produced markedbronchodilation, but no significant differences weredetected between their effects.

IsoetharineIn a randomised single-blind parallel study of

30 days' duration, the efficacy of nebulised salbu­tamol 2.5mg was compared with nebulised iso­etharine 2.5mg in 121 asthmatic patients. On thefirst day of treatment, FEY1 values were signifi­cantly higher in the salbutamol group at all as­sessments from 15 minutes following inhalation (p< 0.05 to p < 0.01). Relative increases from base­line FEY1 values 30 minutes postdose were 43%and 38% for salbutamol and isoetharine, respec­tively. The mean duration of action (~ 15% im­provement in FEYJ> was 4.8 hours for salbutamoland 3.1 hours for isoetharine (p < 0.0 I). Similartrends were seen after administration on the lastday of treatment, although the duration of actionof both drugs was reduced (4.2 hours vs 2.4 hoursfor salbutamol and isoetharine, respectively; p <0.01) [Storms et aL 1986]. Furthermore, inhaledsalbutamol 180~g was found to have a significantlylonger duration of action than inhaled isoetharine680~g in patients with reversible chronic pulmo­nary obstruction (Berezuk et aL 1983).

Isoprenaline (Isoproterenol)In a placebo-controlled double-blind crossover

study in 24 patients with bronchial asthma, in­haled single doses of salbutamol 170~g and iso-

99

prenaline (isoproterenol) 160~g both caused a sig­nificant (p < 0.01) increase in FEY I , FVC, andFEF25-75% 15 minutes after administration. Sal­butamol produced peak increases in FEY1 andFEF25-75% of 45 and 95%, respectively, at 15 min­utes, with a peak improvement of 33% in the FYCoccurring at 2 hours . Isoprenaline, on the otherhand, produced smaller peak responses in FEYI,

FEF25-75% and FYC of 38, 38 and 26%, respec­tively. During the second hour, the improvementin lung function was significantly better with sal­butamol than with isoprenaline (p < 0.01). In ad­dition, the duration of action was considerablylonger with salbutamol (6 vs 2 hours) and side ef­fects were more common with isoprenaline (To­mashefski 1981). Similarly, long term studies of upto 6 months duration have also confirmed that sal­butamol is a superior bronchodilator in patientswith reversible obstructive airways disease afterboth inhaled (Bedell & Richardson 1981 ; Tomash­efski 1981)and nebulised therapy (Light et aL 1984).Moreover, a considerably lower incidence of ad­verse effects (particularly cardiovascular) were ob­served during salbutamol treatment.

Orciprenaline (Metaproterenol)Only a few studies comparing inhaled salbuta­

mol (90 and 180~g) and orciprenaline (1300 and2600j.tg) have been reported in patients with re­versible obstructive airways disease, and no sig­nificant differences were observed with regard tospirometric responses or untoward effects (Ahrenset aL 1987; Berezuk et aL 1983). In addition, bothdrugs caused a similar improvement in airwayfunction in 20 patients with obstructive airwaysdisease who received nebulised solutions of sal­butamol 5mg 3 times daily or orciprenaline 15mg3 times daily for a period of 7 days (Habib et aL1987).

ProcaterolIn a long term (3 months) double-blind study

in 18 patients with bronchial asthma, inhaled sal­butamol 180~g and inhaled procaterol 20j.tg, each3 or 4 times daily, produced rapid and significantbronchodilation. Throughout the study there were

100

no significant differences in efficacy between the 2treatments. The maximum increases in FEY I ondays 1, 14 and 90 were 41.2, 54.9 and 33.7%, re­spectively, with salbutamol, and 43.6, 29.7 and34.0%, respectively, with procaterol (Morin et al.1987). Similarly, there was no significant differencein the degree of bronchodilation produced by oralsalbutamol 2 or 4mg 3 times daily or procaterol0.05 or O.lmg twice daily for 3 months in patientswith bronchial asthma. However, adverse effects,most notably tremor, were significantly (p < 0.05)more common with procaterol (Legris et al. 1987).

TerbutalineNo statistically significant differenceswere found

between the bronchodilatory effects of single oraldoses of salbutamol 4mg or terbutaline 5mg inasthmatic patients. The magnitude and time courseofbronchodilation was equivalent, both drugs hav­ing a durationof action of at least 8 hours . How­ever, significantly fewer (p < 0.5) musculoskeletalside effects (such as tremor) were observed aftersalbutamol (Wolfe et al. 1985). Several well-con­trolled studies in patients with bronchial asthmahave demonstrated that oral salbutamol 4mg 3times daily has an almost equal bronchodilatoryeffect to a sustained release preparation of terbu­taline 7.5mg administered twice daily over a 2-weektreatment period. Both drugs produced increases inFEY I and FVC, but only sustained release terbu­taline significantly (p < 0.05) improved PEF (Bes­kow et al. 1984; Peel et al. 1983). Similarly therewas no significant difference in terms oflung func­tion produced by a controlled release preparationof salbutamol 8mg or sustained release terbutaline7.5mg, both twice daily for 3 weeks in patients withreversible obstructive airways disease (Yiskum etal. 1988). The bronchodilatory effects of intraven­ous salbutamol 250Jlg and terbutaline 500Jlg wereequivalent in patients with reversible airways ob­struction. Both drugs maximally improved pul­monary function at 5 minutes and this was main­tained for approximately 3 hours. However, asignificantly (p < 0.01) higher incidence of adverseeffects (such as palpitations) occurred with salbu­tamol (Sahay et al. 1984).

Drugs 38 (J) 1989

TulobuterolNo statistically significantdifferenceswere found

between the bronchodilatory effects of oral salbu­tamol 4mg 3 times daily and oral tulobuterol 2mgtwice daily, each for a period of 14 days, in patientswith chronic stable asthma (Aguero & Dal-Re1988).

3.2.3 Comparisons with Anticholinergic DrugsTable IY summarises some single-dose com­

parative trials of salbutamol and anticholinergicdrugs in patients with reversible obstructive air­ways disease of varying severity and origin. In gen­eral, the bronchodilatory effects of salbutamol weresuperior to those of atropine methonitrate and ox­itropium, equivalent to those of atropine and ipra­tropium bromide, but, as might be expected, in­ferior to those obtained with a combination ofipratropium bromide and fenoterol.

Atropine and Atropine MethonitrateNo significant difference was found between the

effects of single doses of inhaled salbutamol (0.045mg/kg) or atrop ine (0.035 rug/kg) in asthmaticpatients whose disease originated mainly in thelarge airways. However, in those patients in whomthe small airways made the major contribution tototal airways resistance, atropine produced a sig­nificantly greater increase (p < 0.01) in sGaw

(Molho et al. 1987).In another study, inhalation of salbutamol 100Jlg

was superior to inhaled atropine methonitrate100Jlg in asthmatic patients. Moreover, the 2 drugsused in combination provided additional bron­chodilatory effects, although it was not an additiveresponse except in the case of FVC (Maesen &Smeets 1985).

Ipratropium BromideIn crossover studies of 6 to 8 weeks duration

involving 71 patients with asthma or bronchitis, 3times daily administration of salbutamol 200Jlg andipratropium bromide 40 or 80Jlg produced similarchanges in PEF and other spirometric readings, al­though more patients expressed a preference forsalbutamol (Bellet al. 1982; Posner & Posner 1982).

Salbutamol: A Reappraisal

In 10 patients with chronic partially reversibleairways obstruction nebulised solutions of ipra­tropium bromide (0.125, 0.25 and 0.5mg) and sal­butamol 5mg produced equivalent peak broncho­dilation between I and 2 hours postadministration.However , the duration of action of the 2 higherdoses of ipratropium bromide was significantlygreater (p < 0.05) than salbutamol (Jenkins et ai.198I). In addition, Chan et ai. (1984) reported that,in 20 patients with chronic bronchitis, nebulisedsolutions of ipratropium bromide 0.5mg and sal­butamol 5mg had a similar onset of action andelicited equal bronchodilatory response . However,both the duration and magnitude of bronchodila­tion produced was significantly greater (p < 0.05)when a combination of the 2 drugs was employed.

Ipratropium Brornide/Fenoterol CombinationIn a number of well-controlled single-dose stud­

ies in patients with reversible obstructive airwaysdisease, a combination inhaler delivering ipratrop­ium bromide 40/lg and fenoterol 200/lg has oftenproduced a greater or more prolonged bronchodi­latory response than inhaled salbutamol (200/lg).Moreover, the improvements in FEV I and PEFwere often significantly in favour of the combin­ation , whereas no statistically significant differencehas been demonstrated for FVC between the 2treatments (Crane 1986; Fischbacher et ai. 1984;Flint et ai. 1983; Fontana et ai. 1986; Marangio etai. 1986). Interestingly, in contrast to single-dosestudies , administration of the 2 regimens over aperiod of a few weeks usually only demonstratedslight differences between the combination and sal­butamol in terms of improving respiratory func­tion (Aquilina et ai. 1986; Macaluso & Del Torre1986).

OxitropiumLaitinen and Poppius (1986) compared the ef­

fectiveness of oxitropium bromide (200/lg) plussalbutamol (200/lg) with salbutamol 200 or 400/lgalone, all administered by inhalation in 6 asth­matic patients over a period of at least 28 days.Compared with baseline values all 3 treatmentssignificantly increased morning PEF values (p <

101

0.05). The increases were significantly (p < 0.05)greater after combination and high-dose salbuta­mol than after salbutamol 200/lg. Mean eveningPEF values after the combination were greater (p< 0.05) than those after salbutamol 200 or 400/lg.Similarly , in a single-dose inhalation study involv­ing 12 asthmatic patients, a combination of sal­butamol 200/lg and oxitropium 200/lg produced abetter bronchodilatory response than did either drugadministered alone. However, in the same patients ,inhaled salbutamol 400/lg was found to be superiorto the combination (Tukiainen & Salorinne 1985).

3.2.4 Comparisons with MethylxanthineDerivatives and Their Use in CombinationMethylxanthine derivatives (usually theophyl-

line) and salbutamol have been widely used in Eur­ope and North Am~rica for the treatment of re­versible obstructive airways disease. However, therelative role of these agents used in combinationis still debated (for a more detailed review see Kelly1984). Unfortunately, there have been few well-de­signed long term trials comparing optimal dosagesof methylxanthines and salbutamoi. However , anumber of short term (up to 5 weeks duration)studies have been performed in patients with re­versible obstructive airways disease. In such stud ­ies usual oral doses of salbutamol (4mg up to 3times daily) were as effective as oral aminophylline225 or 450mg daily (Laitinen & Poppius 1982;Leitch et ai. 1981), choline theophyllinate 400mg3 times daily, and theophylline 265mg concomi­tantly administered with hydroxyzine 7.5mg(Alanko & Sahlstrom 1983). Moreover, in a single­dose study involving 17 patients with stable chronicobstructive pulmonary disease, inhaled salbutamol270/lg significantly improved baseline FEV1 (p <0.01) compared with a combination of oral ami­nophylline 400mg and terbutaline sulphate 5mg at30, 60, and 120 minutes after administration (Shim& Williams 1983).

A number of studies in patients with reversibleobstructive airways disease have demonstrated thatcontrolled release oral salbutamol 4mg twice daily

. has an equivalent bronchodilatory effect to a sus­tained release preparation of theophylline (either

102

300mg twice daily or individually titrated to plasmaconcentrations of 10 to 20 mg/L) over treatmentperiods of up to 4 weeks (Britton 1988; Callaghanet al. 1986; Creemers 1988; Kotaniemi et al. 1988;Maesen & Smeets 1986b; Tinkelman 1988; Zeitlin1988). Furthermore, because of its wide margin ofsafety and the fact that plasma concentrationmonitoring is not required , sa1butamol controlledrelease may be preferred to sustained release theo­phylline in clinical practice (Callaghan et al. 1986;Kotaniemi et al. 1988; Zeitlin 1988).

Since 132-adrenoceptor agonist drugs andmethylxanthines act at different receptor sites,combining these 2 classes of drug could reasonablybe expected to result in improved efficacy. Indeed,when oral theophylline was administered in com­bination with inhaled salbutamol (usually 200~g 3or 4 times daily) in patients with reversible ob­structive airways disease of various origins, thecombined treatment produced the greatest im­provement in respiratory function (Barclay et al.1982; Busse et al. 1986; Filuk et al. 1985; Joad etal. 1987; Sahay & Chatterjee 1983; Taylor et al.1985). However, the difference was not always sta­tistically significant.

3.2.5 Salbutamol in Combination withBeclomethasone DipropionateThe efficacy of an inhaled combination of sal­

butamol 150~g and the corticosteroid beclometha­sone dipropionate 100~g has been assessed inpatients with reversible obstructive airways disease(particularly chronic obstructive lung disease). Asmight be expected, single-dose studies have shownthat the combination is no more effective than in­haled salbutamol 200~g alone in terms of improv­ing the acute bronchodilatory response (Dal Negroetal. 1984; Joubert et al. 1985). However, in a 4­week study in chronic asthmatic patients, the si­multaneous administration (4 times daily) of the 2drugs from a combination inhaler (salbutamol200~g plus beclomethasone dipropionate 1OO~g)provided equally effectiveControl of symptoms andairways obstruction as treatment with the samedosages of the 2 drugs administered together butfrom separate inhalers (Pover et al. 1986).

Drugs 38 (J) 1989

In a few poorly controlled comparative studies,the combination of salbutamol and beclometha­sone dipropionate appeared to give more effectiveprotection against chemically induced broncho­spasm than did salbutamol (Pomari et al. 1984),fenoterol (Perri et al. 1985)or theophylline (Arossaet al. 1985).

3.2.6 Comparisons with Other Drugs and/orTheir Use in CombinationA limited number of studies have evaluated the

bronchodilatory effects of calcium antagonists andsalbutamol in patients with reversible obstructiveairways disease. In a randomised double-blind trial,the protective effects of single doses of nebulisedverapamil and nebulised salbutamol against hist­amine-induced bronchoconstriction were com­pared in 16 asthmatics.. While salbutamol gavemarked protection (p < 0.00I), verapamil pro­duced only limited, but still significant (p < 0.05),protection compared with placebo (McIntyre et al.1983).

Equivocal results have been obtained when ni­fedipine was given concomitantly with sa1butamol.Lever et al. (1~84) reported that oral nifedipine20mg, administered 30 minutes before inhaled sal­butamol 200~g, significantly enhanced (p < 0.025)the bronchodilatory response. However, Rolla etal. (1986) reported that increases of sGaw and FEY1

produced by inhaled salbutamol .400~g in 10patients with chronic partially reversible airwaysobstruction were not affected by pretreatment withoral nifedipine 20mg.

A few single-dose studies in small numbers ofasthmatic patients compared the bronchodilatoryeffects of a-adrenergic antagonists alone, and incombination with salbutamol. Gaddie et al. (1981)reported that indoramin 0.2 mg/kg intravenouslydid not produce significant bronchodilation, but incombination with inhaled salbutamol 200~g therewas an increase in FEY1 and FVC which wasgreater than that achieved with salbutamol alone.Similarly, nebulised phentolamine lOmg in com­bination with nebulised salbutamol 2.5mg eliciteda more favourable respiratory response than eitheragent administered alone in patients with asthma.

Salbutamol : A Reappraisal

However, the differences between salbutamol aloneand the combination were not statistically signifi­cant (Shiner & Molho 1983).

A number of studies have evaluated the efficacyof a combination of salbutamol (usually 4mg twicedaily) and the antihistamine oxatomide (30 or 60mgtwice daily) in patients with reversible obstructiveairways disease . Most of the studies were uncon­trolled, contained only small numbers of patients,and were of varying treatment periods (up to 5weeks). The combination appeared to improve res­piratory function and symptoms of the diseasecompared with salbutamol alone, but the clinicalrelevance of these findings remains to be estab­lished , given the limitations of the stud ies men­tioned above (Cogo et al. 1984; Ghiringhelli 1985;Ghiringhelli & Schiavi 1984; Pagliano 1985; Rossiet al. 1984; Seremin & Crapioglio 1986).

3.3 Use in Severe Acute Asthma

The development of an attack of severe asthma(or severe acute asthma) represents a potentiallylethal situation and despite the advances in anti­asthma treatment, which have contributed to thedecrease in morbidity of asthma over the last 30years (Johnson et al. 1984), a similar decrease inthe mortality of asthma has not been achieved.Moreover, deaths continue to occur at a time whena number of apparently suitable drugs are availableto treat acute asthmatic attacks. In general deathcan result from a failure ofdiagnosis, from the speedof onset of the acute attack, from a lack of bothpatient and doctor awareness of the severity of dis­ease, or because of poor drug management of theunderlying disease (for a more deta iled review seeCochrane 1984).

Salbutamol has been used successfully in themanagement of severe acute asthma for many years,and it is the standard emergency treatment for thedisease in a number of countries (Cochrane 1984).However, the best route of administration (nebu­lised or parenteral) remains controversial despite anumber of controlled trials (Fergusson et al. 1983).

103

3.3.1 Nebulised and parenteral SalbutamolNebulised salbutamol (5mg) delivered with or

without intermittent positive pressure breathing(IPPB) has been shown to be superior to the druginhaled in the normal recommended dose (200 and400J-tg) from a pressurised aerosol or as a dry pow­der in patients with severe acute asthma (Tuki­ainen & Terho 1985; Webber et al. 1982). How­ever, in a double-blind crossover trial, Fergussonet al. (1983) reported that nebulisation with IPPBas a means of administering salbutamol was nomore advantageous than passive inhalation in theinitial treatment of 20 patients with life-threaten­ing asthma.

Robertson et al. (1985) evaluated 2 regimens ofnebulised salbutamol in 33 children with acuteasthma. One group ofchildren received salbutamol0.15 mg/kg, up to a maximum of 5mg, at l-hourintervals for a total of 3 doses. The second groupreceived salbutamol 0.15 mg/kg initially then 0.05mg/kg (up to a maximum of 1.7mg) at 20-minuteintervals for a total of 6 doses. The more frequentadministration in the second group resulted in asmoother rise in FEY I to achieve an earlier peakbronchodilatory response which was maintainedthroughout the study. In contrast to the positivebenefit produced by nebulised salbutamol inpatients with severe acute asthma, as reported inthe above clinical trials, Douglas et al. (1985) foundthat in a double-blind dose-ranging study (1.25, 2.5and 5mg) involving 32 patients with severe acuteasthma only the 5mg dose produced improvementin airflow obstruction.

Studies in which parenteral salbutamol wasgiven as the only treatment for severe acute asthmaare limited. Bohn et al. (1984) reported that a con­stant intravenous infusion of the drug reversedsevere bronchospasm in the presence of respiratoryfailure . However, slight increases in heart rate wereseen with increasing infusion rate (as might be ex­pected in view of the drug's effect on tJ-receptorsin the myocardium; see section 1.2). In a more re­cent study Cheong et al. (1988) compared the effectof salbutamol administered as an intravenous in­fusion of 12.5 J-tg/min over 4 hours with 5mg in­haled via a nebuliser hourly in 76 patients with

104

severe acute asthma. PEF was improved signifi­cantly (p < 0.01) more in those patients receivingthe intravenous infusion (25.2%) than in the ne­buliser group (14.3%).

3.3.2 Comparisons with Other Drugs and/orTheir Use in CombinationIn comparative clinical trials involving patients

with severe acute asthma salbutamol was more ef­fective than adrenaline (epinephrine), aminophyl­line or sodium cromoglycate (cromolyn sodium),and as effective as terbutaline and ipratropium(table V).

In children suffering from severe asthma, ne­bulised salbutamol was found to be more effectiveand produced fewer side effects than adrenaline ad­ministered intramuscularly (Turpeinen et al. 1984)or subcutaneously (Becker et al. 1983). Similarly,in a placebo-controlled double-blind crossoverstudy in adults , subcutaneously administered sal­butamol was superior to subcutaneous adrenalinein terms of both the extent and the duration of itsbronchodilatory effects (Busse et al. 1984).

Intravenous salbutamol up to 0.3mg was a moreeffective bronchodilator and produced fewer sideeffects than intravenous aminophylline up to 400mg(Greif et al. 1985; Senderovitch et al. 1984). In ad­dition, Senderovitch et al. (1984) reported that acombination consisting of lower doses of salbuta­mol and aminophylline produced effective bron­chodilation within 1 hour of treatment which lastedfor up to 4 hours. The combination appeared to beas effective as higher doses of salbutamol admin­istered alone and tended to be better tolerated (seetable V). Salbutamol and terbutaline, both 0.25mgsubcutaneously, were equally effective in adultpatients with severe acute asthma and as effectiveas adrenaline 0.25mg administered subcutaneously(Hoernke et al. 1985; Kemp et al. 1985). In addi­tion , Kemp et al. (1985) also reported that sub­cutaneous salbutamol 0.5mg produced better pul­monary responses than terbutaline and adrenaline(both 0.25mg), but there was a higher incidence ofside effects with this dosage.

In a group of acutely ill asthmatic patients Leahyet al. (1983) found salbutamol 5mg and ipratrop-

Drugs 38 (l) 1989

ium lmg, each by nebulisation , to be equally ef­fective. However, salbutamol produced a furthersignificant (p < 0.01) rise in PEF when given 1hour after ipratropium; this did not occur whenipratropium was given 1 hour after salbutamol.

Ward et al. (1984) reported a study in whichsalbutamol 10mgby nebulisation , followed 2 hourslater by ipratropium 0.5mg, elicited a greater andmore significant increase in PEF (p < 0.05) than 2doses of salbutamol (2 x lOmg by nebulisation; 2hours apart) in 24 adult patients.

3.4 Use in Childhood Asthma

Asthma appears to be relatively common inchildhood and community surveys have shown thatup to 11 %of all children may have asthma at somestage of their development (Lee et al. 1983). Un­fortunately in many instances the disease is notcorrectly diagnosed, and it has been suggested thatmuch unnecessary distress could be avoided if doc­tors would follow the maxim that in childhood allrecurrent wheezing is due to asthma until provedotherwise. The recurrent coughing associated withasthma nearly always responds rapidly to appro­priate treatment, a feature noticeably absent whencoughing results from other causes (for a more de­tailed review see Milner 1984).

Response to bronchodilators is generally morerapid and more complete in children than in adults,so these drugs form the first line of therapy for allasthmatic children, whether they have only veryoccasional attacks or severe, chronic symptoms.This rapidity of response is accompanied by a re­markably low incidence of side effects comparedwith incidence rates in adults, indicating a high levelof tolerability (Milner 1984).

3.4.1 Comparisons with PlaceboThe efficacy of salbutamol compared with pla­

cebo has been clearly demonstrated in a numberof studies in children. In both acute and longer termstudies statistically significant improvements inrespiratory function have been reported , irrespec­tive of the route of admin istration or formulationused (Berg et al. 1981 ; Chang et al. ·1985; Dawson

Salbutamol: A Reappraisal

Table V. 8tudies compa ring salbutamol (8) with other bronchodilators in patients with severe acute asthma

105

Reference No. of pts Dosage , route Improvement in Adverse effectsb Overall efficacy and comments?

lung funct ions

Becker et al. 40 C 80.1 mg/kg Neb 8 =- Adr 8 < Adr 8 > Adr due to non-invasive

(1983) Adr 0.Q1 mg/kg 8C method of administration and

better tolerabil ity

Busse et al. 20 A 8 0.5mg 8C 8 ~ Adr 8 =- Adr 8 > Adr

(1984) Adr 0.3mg 8C

Greif et al. (1985) 21 A 8 0.004 mg/kg IV 8 > Ap 8 ~ Ap 8 ~ Ap

Ap 6 mg/kg IV

Hasham et al. 20 C 8 5mg Nebd 8 > 8CG NO 8 > 8CG

(1981) 8CG 20mg Nebd

Hoernke et al. 20 A 8 0.25mg 8C 8=-T 8=-T 8=- T

(1985) T 0.25mg 8C

Kemp et al. (1985) 18 A 8 0.125-0.5mg 8C 80.5 > 80.25 =- T 80.5 > 80.25 ssa T 80.25=- T. 80.5 produced best

T 0.25mg 8C =- Adr =- Adr pulmonary response, but most

Adr 0.25mg 8C side effects

Leahy et al. 12 A 8 5mg Nebs 8 ssa Ip 8 =- Ip 8 ses Ip. 8 produced significant

(1983) Ip 1mg Nebs furt her improvement when given

1 hour after Ip

8enderovitch et 45 8 0.3mg IV 8=-8+Ap ~ 8 ~Ap ~8+Ap 8 + Ap would seem to be the

al. (1984) Ap 400mg IV Ap most useful treatment combining

8 0.15mg IV + efficacy with good tolerability

Ap 200mg IV

Turpe inen et al. 46 C 8 0.075-0.15 mg/kg 8 > Adr 8 ess Adr 8 > Adr(1984) Neb

Adr 0.006-0.01 mg/kg

1M

Ward et al, (1985) 24 A 8 10mg Neb + 8 8 + Ip > 8 + 8 8 + Ip < 8 + 8 If after an initial dose of 8 fur-

10mg Neb! ther bronchodilation is needed it

8 10mg Neb + Ip is best achieved using Ip rather

0.5mg Neb! than a repeated dose of 8

a Based on pulmonary function tests . 8 > indicates salbutamol produced significantly greater improve ments in lung function;

8 ~ indicates that salbutamol tended to be superior to the comparator drug ; =- indicates that salbutamol was as effective as

the compa rator drug .

b Usually in terms of card iovascu lar parameters and tremor. 8 < indicates that salbuta mol prod uced fewer adverse effects;

8 ~ indicates salbutam ol tended to produce fewer adverse effects; saa indicates that salbutamol and the comparator drug produced

similar adverse effects.

c 8 > indicates that salbutamol was the preferred treatme nt; 8 ~ indicates that salbuta mol tended to be the preferred treatment;

=- indicates bot h treatments were equally preferred.

d Drugs were given as part of treatment sequences: placebo, 8 and 8CG, or placebo, 8CG and 8. Only data from the first active

treatment periods have been compared .

e Drugs were given as part of treatment sequences: 8 followed 1 hour later by Ip, and Ip followed 1 hour later by 8 . Only data

from the first active treatment periods have been compared.

f The .second dose was administered 2 hours after the first dose.

Abbreviations: C = children; A = adults; Adr = adrena line; Ap = aminophylline; 8CG = sodium cromoglycate (cromolyn sodium) ;

T = terbutaline; Ip = ipratropium bromide; Neb = nebulised; IV = intravenous; 8C = subcutaneous; 1M = intramuscula r;

NO = no details provided.

106

et al. 1986; Prendiville et al. 1987; Rachelefsky etal. 1981 , 1982).

In a double-blind crossover study in 10 childrenwith asthma, single doses of both oral (0.1 mg/kg)and inhaled (1OO~g) salbutamol significantly (p <0.005) increased lung function (FEVI, FVC and VC)when compared with placebo. Furthermore, com­bined oral and inhaled treatment with salbutamolresulted in significantly greater increases in FEV1

and VC (both p < 0.01) and FVC (p < 0.05) whencompared with oral therapy alone, and a signifi­cantly higher FEV1 (p < 0.01) when compared withinhalation therapy alone (Berg et al. 1981). Simi­larly, in a 3-month clinical trial a combination ofinhaled (400~g) and oral (4mg) salbutamol 3 timesdaily was superior to inhaled salbutamol alone. Inother placebo-controlled studies inhaled salbuta­mol (200~g) increased PEF (11.3 vs 2.8%) in asth­matic children (Chang et al. 1985), while nebulisedsalbutamol (2.5mg)was effective in abolishing hist­amine-induced bronchospasm in wheezy infants(Prendiville et al. 1987).

Rachelefsky et al. (1982) examined the efficacyof tablet and syrup formulations of salbutamol inthe treatment of childhood asthma in a 2-phasetrial. During the first phase the children were treatedwith placebo and salbutamol 2, 4 and 6mg (as eithertablets or syrup) 4 times a day for 1 week each insingle-blind fashion. All active treatments were ef­fective compared with placebo, the 4mg and 6mgdoses superior to the 2mg dose. In the second phase,a double-blind placebo-controlled crossover study,salbutamol 4mg administered in a syrup formu­lation produced a greater maximal bronchodilatoryresponse than the same dose of salbutamol admin­istered as a tablet formulation, both formulationsbeing administered 4 times a day for 1 week.

3.4.2 Comparisons with Other132-AgonistsThe efficacy of salbutamol and other fh-adreno­

ceptor agonists have been compared in childhoodasthma (table VI). Inhaled salbutamol 100 and200~gproduced bronchodilation for up to 6 hours,which was greater than that produced by compar­able doses of isoprenaline 70 and 140~g (Littner etal. 1983).

Drugs 38 (1) 1989

Compared with terbutaline 500~g administeredvia a 'Misthaler', salbutamol 200~g administeredin powder form via a 'Rotahaler' significantly im­proved (p < 0.05) both FEV1 and PEF, and therewas also a trend for salbutamol to cause greaterbronchodilation throughout the study (Towns et al.1983).

No clinically significant difference was seen be­tween usual single oral and inhaled doses of fen­oterol and salbutamol in terms of bronchodilatoryeffectivenessand duration of action (Asher & Dunn1985; Dawson et al. 1985; Van Asperen & Man­glick 1986; Vazquez et al. 1987). Holt and Bolle(1983) also found little or no clinical difference be­tween inhaled fenoterol and nebulised salbutamolwhen administered to children fora short period(3 weeks). A rapid improvement in bronchial ob­struction occurred with both drugs; relative PEFincreased by an average of 20% after 30 minutes,the rise being slightly greater with salbutamol.

In a randomised double-blind study, single oraldoses of salbutamol 125 ~gjkg and procaterol 1.25~gjkg afforded the same degree of protection againstmetacholine- induced bronchospasm in children .Protection of large and medium airways lasted forabout 5 and 7 hours, respectively, for the 2 drugs;procaterol seemed to be more protective in smallairways although the difference was not statisti ­cally significant (De Candussio et al. 1986).

3.4.3 Comparisons with OtherDrugs andTheir Use in CombinationIn a randomised double-blind crossover study

in 48 children with asthma, combining a nebulisedsolution of salbutamol 48 ~gjkg with ipratropiumbromide 215 ~gjkg did not significantly improvepulmonary function as compared with salbutamolalone (Boner et al. 1987). However, increases inFEV1 and FEF25-75 following the combination werealmost double those after ipratropium bromidealone. Moreover, there was no significant differ­ence in respiratory responses when the combina­tion was given in half versus full doses.

Lee and Evans (1982) compared the broncho­dilator efficacy and incidence of side effects of in­haled salbutamol 270~g with those of orally ad-

Salbutamol: A Reappraisal 107

Table VI. Summary of some single-dose or short term double-blind crossover trials comparing salbutamol (S) with other commonly

used bronchodilators in children with asthma

Reference No. of pts Dosage, route Parameters

assessed

Overall resulta Comments

Comparisons with f:l-agonists

De Candussio et 12 S 125 ltg/kg PO FEV" FVC, S ssa Pc

al. (1986) Pc 1.25 ltg/kg PO MEFso, MEF2S

Holt & Bolle 17 S 75 ltg/kg qid x 3 PEF S~F

(1983)b weeks Neb

F 200"g tid x 3weeks Inh

Llttner et al. 11 S 100, 200"g Inh sGaw, TGV, FEV" S > Is

(1983) Is 70, 140"g Inh FVC

Towns et al. 25 S 200"g Inh FEV" PEF S >T(1983) T 500"g Inh

Van Asperen & 12 S 200 ltg/kg PO FEV" PEF S==FManglick (1986) F 200 ltg/kg PO

Vazquez et al. 22 S 4mg PO PEF S==F

(1987) F 5mg PO

Comparisons with other bronchodilators

Boner et al. 48 S 48 ltg/kg Neb FEV" FEF2S-7S S == S + Ip > Ip

(1987) Ip 215 ltg/kg NebS + Ip Neb

Lee & Evans 19 S 270"9 Inh FEV" FVC, PEF S+The ""S >(1982) The 7.5 mg/kg PO The

S + The

Pierson et al. 17 The 12-28 mg/kg/day PEF, symptom S + The > The(1985) x 2 weeks PO scores

S 1 mg/kg qid x 2

weeks PO

Procaterol appeared to protect

small airways for longer

6 patients failed to complete the

study

Is caused a greater incidence of

adverse effects

Over 70% of the children in the

study preferred salbutamol'Rotahaler' to terbutaline

'Misthaler'

F caused a greater incidence of

increased heart rate

Half doses of the S + Ip

combination equivalent to S + Ip

full dose

2 patients failed to complete thestudy. 8 of 17 patients receivingThe reported 1 or more sideeffects

Disadvantage of SjThe therapy

may be a delay in seeking

medical help for acute severeasthma

a ssa indicates that S was as effective as the comparator drug; S ~ indicates that salbutamol tended to be superior to the comparator

drug; S > indicates salbutamol was superior to comparator drug.b Non-blind.

Abbreviations: Pc = procaterol; Is = isoprenaline; T = terbutaline; F = fenoterol; Ip = ipratropium bromide; The = theophylline ; PO

= oral; Neb = nebulised; Inh = inhaled; qid = 4 times daily; tid = 3 times daily; FEV, = forced expiratory volume in 1 second; FVC= forced vital capacity ; PEF = peak expiratory flow; MEFso = maximal expiratory flow at 50% of vital capacity; MEF25 = maximalexpiratory flow rate at 25% of vital capacity; FEF25-75 = forced expiratory flow between 25 and 75% of vital capacity; TGV = thoracicgas volume; sGaw = specific airways conductance .

ministered theophylline 7.5 mg/kg and acombination of the 2 drugs in 19 children with sta­ble asthma. Following salbutamol , FEY I reached amaximum of 50.2% above baseline values at 60

minutes, and this was markedly reduced by 120minutes . Following theophylline, maximum FEYI

was 33.2% above baseline values at 120 minutes.The combination regimen resulted in a signifi-

Fig. 5. Mean percentage improvement in forced expiratoryvolume in I second (FEV I) after inhaled salbutamol 270!'g(e), oral theophylline 7.5 mg/kg (.) and a combination ofthe two regimens (0) in 19 children with stable asthma (afterLee & Evans 1982).

108

~ 60~e...;;wIL

.6 40

EQ)

EQ)e20a..;sQ)

::E60 120

Time (minutes)

180 240

Drugs 38 (l) 1989

Trabacco 1984), respiratory function evaluated interms of PEFR also showed the combination to besignificantly superior (Bianchi 1985).Additionally,the combinat ion reduced dyspnoea attacks, and wasgenerally well tolerated during these short termstudies.

Brief results have been published of a 16-weekdouble-blind crossover study in 18 asthmaticchildren which compared the clinical efficacy ofregular inhalations of salbutamo l 200 to 300j.Lg 3or 4 times daily and beclomethasone dipropionate100 to 150j.Lg 3 or 4 times daily administered eitherfrom a combination inhaler or from separate in­halers (Hambleton et al. 1987). Both regimens con­trolled asthmatic symptoms throughout the trialand, as might be expected, there were no signifi­cant differencesbetween daily PEF, symptom scoresor incidence of side effects between the two.

cantly greater improvement in FEV I than eitheragent administered alone, and it also had an ex­tended duration of action, the response continuingunabated for at least 4 hours (fig. 5). However, thecombination was associated with a higher inci­dence of side effects, such as gastrointestinal com­plaints , dizziness and palpitation, which were pre­sumed to be due to theophylline.

The addition of salbutamol syrup 0.4 mg/kg 4times daily for 2 weeks to 'optimum' theophyllinethera py in 17 children with chronic asthma sig­nificantly improved pulmonary function as meas­ured by PEF (p < 0.01) and diminished symptomscores (p < 0.02) compared with those receivingtheophylline alone. Moreover, the concurrent useof salbutamol was not associated with any increasein adverse effects. The theophylline group also re­quired significantly (p < 0.01) higher plasma con­centrations of theophylline to control their asthma;10.5 mg/L versus 5 mg/L (Pierson et al. 1985).

In a limited number of short term (approxi­mately 3 weeks duration) non-blind studies inchildren, the combi ned use of oral salbutamol withoxatomide (antihistamine) usually resulted in agreater or more prolonged response than occurredwith salbutamol alone. Although the efficacy of thecombination was generally only assessed by symp­tom scores (Bianchi 1985; Mangiaracina et al. 1985;

3.5 Use in Exercise-Induced Asthma

It has long been known that exercise can pro­voke an attack of asthma in susceptible individualsalthough, despite considerable recent research, theunderlying mechanisms involved in this phen­omenon have not been fully elucidated. As a symp­tom it occurs in patients of all ages but it seems tobe particularly troublesome in younger, more ac­tive subjects. While some patients never exercisestrenuously enough to suffer such attacks, most datasupport the view that the majority of asthmaticsdo, and between 70 and 90% experience some de­gree of postexercise bronchospasm (for more de­tailed reviews see Godfrey 1982, 1984).

Exertional asthma is generally self-limiting, andtreatment is directed towards prophylaxis usingvarious oral and inhaled medications , and identi­fying where possible any specific aetiological factorthat causes the airways hyperresponsiveness whichleads to the exercise-induced asthina. In the past,drugs such as sympathomimetic agents, antichol ­inergics, methylxanthines and sodium cromogly­cate have been used to prevent exercise-inducedbronchospasm. Salbutamol administered by inhal­ation has been shown to be an extremely effectiveagent in the prophylaxis of exertional asthma

Salbutamol: A Reappraisal 109

(Godfrey 1982, 1984; Konig 1981 ; McFadden &Mills 1986; Scherrer & Kyd 1981). In terms of pro­tecting against abnormal pulmonary response toexercise, a single inhalation of salbutamol 180 or200/lg was superior to sodium cromoglycate (Konig1981; Marshall et al. 1985; Rohr et al. 1987; Spadaet al. 1984), theophylline and atropine (Konig 1981),inhaled orciprenaline (Berkowitz et al. 1986) andinhaled ipratropium bromide (Spada et al. 1984).Tabas et al. (1985) reported that salbutamol 4mgorally was somewhat less effective than oral sod­ium cromoglycate 20mg in controlling exercise-in­duced asthma, and this concurs with previous datawhich suggest that inhalation may be the route ofadministration of choice (for a review see Godfrey1984). Comparing dry powder and nebulised so­lution inhalation of salbutamol and/or sodiumcromoglycate for the prophylaxis of exercise-in­duced bronchospasm in 16 children, Bundgaard(1986) demonstrated that salbutamol alone wassignificantly superior to sodium cromoglycate, andlittle further protection was afforded by combiningthe 2 drugs (fig. 6). It has also been shown thatcontrolled release salbutamol 4mg orally and sus­tained release theophylline (individually titrated)are equally effective in preventing exercise-inducedbronchospasm in asthmatic children (Tsanakas &Baxter 1988).

There have been few published studies com­paring the relative efficacy of the different selectiveIh-adrenoceptor agonists in protecting against ex­ercise-induced asthma, and there seems to be little

to choose between drugs such as salbutamol, ter­butaline and fenoterol (Godfrey 1984). In a smallstudy involving 12 patients with extrinsic asthma,both fenoterol 400/lg and salbutamol 200/lg ad­ministered by dry powder inhalation provided sig­nificant protection against exercise-induced bron­choconstriction. At these dosages there wasevidence that fenoterol produced a superior bron­chodilating effect to salbutamol (Sturani et al. 1983).In a double-blind placebo-controlled crossoverstudy in 24 asthmatic children, salbutamol 200/lgadministered from a dry powder inhaler and ter­butaline 250/lg delivered by a pressurised aerosolwith a tube spacer both gave the same degree ofprotection against exercise-induced bronchospasm(Pedersen 1985). The duration of protection fromexercise-induced asthma by inhaled salbutamol200/lgwas shown to vary widely (2 to 6 hours) in6 stable asthmatic patients (Higgs & Laszlo 1983).However, the addition of inhaled reproterol Imgextended the duration of salbutamol's protectiveeffects as estimated by a significantly lesser reduc­tion in PEF.

4. Therapeutic Studies in Preterm Labour

In the past, infants weighingless than 2.5kgwereconsidered to be premature, however this fails totake into account those low birthweight infantswhose birthweights were reduced as a result of in­trauterine growth retardation and who were deliv­ered near to term. The World Health Organization

Nebulisedsolution

20

30

10

Dry powderinhalation

0­~30u..wc,

.s~ 20

E"E.~ 10E

~:2 0 0 L.L-.JI....Io<::...::;I_

Placebo SCG S SCG Placebo SCG S SCG20mg 0.4mg + 20mg 2.5mg +

S S

Fig. 6. Comparative efficacy of salbutamol (S) and/or sodium cromoglycate (SCG) administered by dry powder or nebulisedsolution inhalation to 16 children in 2 double-blind placebo-controlled crossover trials (after Bundgaard 1986).

110

has therefore defined a preterm infant as one beingborn after less than 37 completed weeks' gestation(Gough 1982).

,B-Sympathomimetic agents such as salbutamolcause myometrial relaxation and as a result of thismay be useful in the treatment of premature labour(Gummerus 1985). However, the value of salbu­tamol in this clinical area remains to be fully con­firmed, as only a limited number of studies havebeen performed . Gummerus (1981) reported datafrom 54 patients with imminent premature labourin the 34th to 36th week of pregnancy who weretreated with an intravenous infusion of salbutamol12 to 50 JLg/min up until 12 hours after cessationof uterine contraction. The therapy was continuedwith salbutamol 4mg orally at 4-hourly intervals.The duration of pregnancy was prolonged by over7 days in 67% of patients, and to at least 37 weeksin 61% of patients; birthweight was over 2.5kg in72% of cases.

Gummerus (1985) reviewed data obtained overa period of 10 years during which time 645 patientswere treated with 6 different ,B-sympathomimeticdrugs for threatened preterm labour during weeks24 to 36 ofgestation. 120 of these patients receivedsalbutamol (dose unspecified); 60% of women hadpregnancies of 37 weeks or more, and 73% of ba­bies had a birthweight greater than 2.5kg. Thosepatients receiving alternative ,B-sympathomimeticsgenerally had similar outcomes to their pregnan­cies. Edmonds and Letchworth (1982) reported thatthe prophylactic use of salbutamol (4mg orally every6 hours) from the fourteenth week of pregnancyhelped prevent preterm labour in 2 patients whohad previous histories of spontaneous abortion.

5. Adverse Effects

After nearly 20 years of clinical use salbutamolhas emerged as a very well-tolerated treatment forthe majority of patients suffering from reversibleobstructive airways diseases.

Other than hypersensitivity reactions, which areextremely rare with salbutamol, the adverse effectsare a predictable extension of its pharmacology. Thefrequency of adverse effects is not only dependent

Drugs 38 (JJ 1989

on dose, and therefore on the route of administra­tion, but also on ,B2-adrenoceptor selectivity. Ad­verse effects are much more common during intra­venous, nebulised and oral therapy than duringinhalation treatment (Shenfield et al. 1984). Al­though generally infrequent, the principal adverseeffects of the drug are tachycardia, palpitation,tremor, peripheral vasodilation, nervousness andmetabolic effects. Nausea, vomiting, increased ap­petite, muscle cramps, increased or decreased bloodpressure, sweating, dilated pupils, angina, head­ache, vertigo, central stimulation, hyperactivity,excitement, irritable behaviour, insomnia, epis­taxis, weakness and dizziness may also occur veryrarely (AHFS Drug Information 1987). The dis­cussion below is only concerned with the principaladverse effects of salbutamol. However, it also in­cludes a section on tolerance (tachyphylaxis) sincethis is an area of considerable debate during longterm treatment with ,B2-agonists.

5.1 Cardiovascular-Related Adverse Effects

Although tachycardia can occur, particularlyfollowing oral, nebulised and intravenous admin­istration of salbutamol, it rarely if ever constitutesa threat to the patient's health. However, a smallnumber of more serious cardiovascular adverse ef­fects can occur.

In a single-blind crossover study lasting 14 days,Al-Hillawi et al.( 1984) studied the incidence ofcardiac arrhythmias in 16 asthmatic patients fol­lowing the daily administration of salbutamol(lOO~g inhaled as required or 8mg orally once daily)or terbutaline (250~g inhaled as required or 7.5mgorally twice daily). Five patients developed ar­rhythmias after salbutamol administration and 3after terbutaline. However, Martelli et al. (1986)were unable to show any arrhythmogenic activityfollowing inhalation of salbutamol (200~g 4 timesdaily) by asthmatic patients, and it seems unlikelythat such low doses could precipitate arrhythmias.It has been reported that nebulised solutions of sal­butamol may aggravate angina in predisposedpatients (Neville et al. 1982), and electrocardio­graphic changes of myocardial ischaemia have been

Salbutamol: A Reappraisal

observed during intravenous salbutamol therapy(Arulkumaran et al. 1986). Moreover, the devel­opment of pulmonary oedema has been shown tobe related to the administration of salbutamol whenused as treatment for premature labour (Hawker1984a,b).

5.2 Tremor

The most common adverse effectassociated withsalbutamol usage is skeletal muscle tremor, whichfrequently requires dosage reduction during longerterm oral therapy. However, there have been fewquantitative clinical studies of tremor. Jenne et al.(1986) compared the initial tremor response toorally administered salbutamol (4mg) and terbu­taline (5mg) in 20 patients with severe obstructiveairways disease. Longer term tremor responses wereevaluated after 3 weeks' treatment with the 2 drugsbeing administered 3 times daily. Initial posturaltremor increased 11.2 relative units for salbutamoland 32.8 units for terbutaline. After 3 weeks'therapy, baseline tremor for both drugs was ele­vated even at 16 hours after the last dose, but re­sponses to a single-dose challenge were much lessthan seen initially; 3.4 units for salbutamol and 9.1units for terbutaline.

5.3 Adverse Metabolic Effects

There have been many reports documenting themetabolic effects of salbutamol ; the majority havebeen concerned with the hypokalaemic effects ofthe drug, although hyperglycaemia and hyperin­sulinaemia do occur rarely (see section 1.4).

Rohr et al. (1986) compared the effects of intra­venous (250Jtg), intramuscular (500Jtg) and sub­cutaneous (500Jtg) salbutamol on plasma potas­sium and glucose concentrations in 21 asthmaticpatients in a single-dose double-blind placebo-con­trolled crossover study. Five subjects assigned tothe subcutaneous group received subcutaneous ad­renaline in a single-blind fashion on a third studyday. The 3 salbutamol routes of administration re­sulted in similar decreases in plasma potassiumconcentrations compared with placebo. The onset

III

of hypokalaemia occurred by 15 minutes and themean maximum decrease compared with placebowas 0.6 mliq/L; although 1 of the intramuscularpatients had a fall of 1.7 mliq/L, Although thehypokalaemic response resolved with time, plasmapotassium concentrations remained significantlydecreased (p < 0.05) compared with placebo at 3hours.

Significant increases in plasma glucose concen­trations were also observed in all 3 treatmentgroups. However, a more marked increase oc­curred in patients receiving salbutamol subcutan­eously or intramuscularly than in those given thedrug intravenously; mean maximum increase fromplacebo was 30 mg/dl in the intramuscular andsubcutaneous groups and 16 mg/dl for the intra­venous group. The onset of this increase in plasmaglucose concentrations was noted within 15 min­utes and was diminishing within 2 hours.

The effects of subcutaneous adrenaline onplasma glucose and potassium concentrations weresimilar to those of salbutamol.

Since the doses of salbutamol employed in thisstudy are those commonly used in clinical practice,the drug should be used with caution in patientswith pre-existing borderline or low plasma potas­sium concentrations, as the magnitude of the po­tassium shift could prove dangerous in isolatedcases.

5.4 Tolerance

It has been postulated for over 20 years that (3­agonist drugs might cause worsening of asthma byinducing 'tolerance' (or alternatively , tachyphyl­axis) to their action. The ultimate outcome of thisprocess could be asthma completely unresponsiveto both endogenous and exogenous (3-adrenoceptorstimulation.

Controversy exists concerning possible toler­ance developing during salbutamol therapy, and alarge number of studies have been performed inasthmatic patients and healthy volunteers (tableVII) to show its likely clinical significance; how­ever, the issue remains to be resolved. Conolly etal. (1982) were able to show the development of

112

Table VII. Summary of some selected tolerance studies in asthmatic patients and healthy volunteers

Drugs 38 (l) 1989

Reference No. and type of Study Dosage, duration, Lung function Comments

subjects design route parameter

assessed

Studies which show development of tolerance

Conolly et al. 5 healthy volunteers; nb S 200"g qid x 4 sGaw, Tolerance with both T and S in both(1982) 5 asthmatics weeks Inh MEF40% (P). volunteers and asthmatics to sGaw, but

T 40-320"g SC PC20, PC35 not MEF40% (P). A slight reduction inperipheral blood lymphocyte s-receotordensity was also observed

Harvey & 6 healthy. non-atopic; nb S 100"g qid x 1 sGaw, FEV1, Normal subjects showed a progress iveTattersf ield 6 non-asthmatic, week Inh PEF reduction in bronchodilator response.(1982)a atopic; S 300"g qid x 1 Atopic subjects. both asthmatic and

8 asthmatic, atopic week Inh non-asthmatic, showed no reduction in

S 400"g qid x 1 bronchodilator responseweek Inh

S 500"g qid x 1week Inh

Repsher et al. 140 asthmatics db, mc S 170"g qid x 13 FEV1 , FVC, Most tolerance to S developed in the

(1984) weeks Inh MMEF 4th week, a small increment after the

Is 150"g qid x 13 8th week of therapy, but no furtherweeks Inh increase by the 13th week. Tolerance

occurred to acute bronchodilating

effect. No tolerance developed to Is

Studies in which no tolerance developed

Higgs et al. 12 healthy. non- nb S 500"g qid x 10 sGaw• FEV1 No evidence of the development of1982) atopic days Inh tolerance

S 100-500"9 qid x 4weeks Inh

Keaney et al. 5 healthy volunteers nb S 200"g qid x 2 sGaw, Vmax 25,(1980) weeks Inh FEV1

S 500" g qid x 2weeks Inh

Lowhagen et 13 asthmatics r, db. S 2.5mg tid x 3 Unspecifiedal. (1982)a co. pc weeks Neb

Repsher et al. 32 asthmatics dp, pr S 170"g qid x 13 FEV1 , FVC, No tolerance developed to S or Is,(1981) weeks Inh MMEF however patients preferred S due to

Is 150"g qid x 13 fewer adverse effectsweeks Inh

a Study involved histamine bronchoprovocation.

Abbreviations : S =salbutamol; T = terbuta line; Is = isoprenaline; nb =non-blind; db =double-blind; mc =multicentre; r = randomised;co =crossover ; pc = placebo-controlled ; pr = prospect ive; qid =4 times daily; tid =3 times daily; Inh = inhaled; SC = subcutaneous;Neb =nebulised; sGaw = specific airways conductance; MEF40%(P) =maximum expiratory flow rate at 60% below total lung capacity;PC20 = provocative concentration of histamine causing a 20% fall in FEV1 in asthmatics; PC3S = provocat ive concentrat ion ofhistamine causing a 35% fall in MEF40%(P) in normal subjects; FEV1 = forced expiratory volume in 1 second; PEF 'T peak expiratory

flow; FVC = forced vital capacity; MMEF = maximum mid-expiratory flow rate; Vmax 25 = maximum flow volume loop.,

Salbutamol: A Reappraisal

tolerance in healthy subjects and patients withasthma following a 4-week course of inhaled sal­butamol, and suggested it was due to the devel­opment of selective subsensitisation of J3-adreno­ceptors in the larger central airways. A greater lossof protection against histamine-induced broncho­spasm was seen in the asthmatic patients in thisstudy.

Repsher et al. (1984) also reported tolerance tothe bronchodilatory effects of inhaled salbutamol170JLg compared with isoprenaline 150JLg, both 4times daily, in a 13-week study in asthmaticpatients . It also appeared that the greatest atten ­uation of activity occurred during the first 4 weeks,and there was only a further small decrease after8 weeks; no further tolerance developed after 13weeks of salbutamol therapy. However, in a 4-weekdose-response study, healthy non-atopic volunteersdeveloped tolerance whereas asthmatic and non­asthmatic atopic volunteers did not (Harvey &Tattersfield 1982).

In contrast to the studies cited above, a numberof trials have failed to demonstrate the develop­ment of tolerance to inhaled or oral (controlled re­lease) salbutamol in either healthy subjects or asth­matic patients (Higgset al. 1982; Keaney et al. 1980;Lowhagen et al. 1982; Repsher et al. 1981 ; Tsan­akas et al. 1988).

It is therefore difficult to assess the importanceof salbutamol tolerance until more definitive in­formation from longer term clinical trials is avail­able. Although several studies indicate that someattenuation of the activity of salbutamol may oc­cur, it must be remembered that tolerance as meas­ured in most of these studies did not mean com­plete loss of the bronchodilating effect of the 13­agonist; i.e. absolute tolerance does not appear todevelop during treatment with salbutamol.

6. Dosage and Administration

Salbutamol is available in a wide range of form­ulations for the management of the various formsof reversible obstructive airways disease andthreatened premature labour . The recommendeddosage instructions are summarised in table VIII.

113

Full details of correct inhaler dosage, which cansignificantly affect the bronchodilatory responseobtained, are beyond the scope of this review andthe reader is directed to obtain the appropriate pre­scribing information (package insert).

Salbutamol is contraindicated in patients hy­persensitive to sympathomimetic drugs. The drugshould be used with caution in patients with hyper­thyroidism, diabetes mellitus, cardiovascular dis­orders (including coronary insufficiency, cardiacarrhythmias and hypertension), and in those beingtreated with monoamine oxidase inhibitors or tri­cyclic antidepressants. Patients should be warnedthat reduced efficacy is generally an indication thattheir asthma is getting worse and they need morebronchodilation. Alternative therapy is then indi­cated since there is the likelihood of a more severeform of asthma being present.

7. Place of Salbutamol in Therapy

Since its introduction almost 20 years ago sal­butamol has become well established in the treat­ment of bronchospastic diseases. Indeed in mostpatients an inhaled J32-agonist such as salbutamolis the 'first-line' treatment of reversible obstructiveairways disease.

Studies with inhaled salbutamol have shown itto be a rapidly acting bronchodilator, with a rela­tively long duration of action, and at least as ef­fective as most ofthe currently available J32-agon­ists. Similarly, orally administered salbutamol hasbeen shown to be an effective and safe broncho­dilator, although not as efficacious as when ad­ministered by the inhaled route. However, thisformulation of salbutamol offers a reliable altern­ative to those patients who are unable to coordi­nate the use of pressurised or metered dose inhal­ers. The parenteral formulations of salbutamol aregenerally reserved for the treatment of life-threat­ening severe acute asthma, and although this routeof administration is often associated with dose-de­pendent adverse effects (most notably tachycar­dia), it has often been shown to be more effectivethan most of the other currently available treat­ments such as adrenaline and methylxanthines.

114 Drugs 38 (l) 1989

Table VIII. Recommended dosages for salbutamol formulations

Clinical use Aerosol Dry powder Nebuliser Oral Parenteral

(lIg) inhaler (mg) (mg)

(lIg)sub- intra- intra-cutaneous muscular venous

(lig/kg) (lig/kg)

Relief of acute A 100-200 A 200-400 2.5-5 NA 88 88 4l1g/kgb

bronchospasm or C 100 C 200intermittentepisodes ofasthma

Prevention of A 200 A 400 NA NA NA NA NAexercise- induced C 100 C 200

asthma

Prophylaxis A 200, 3 or 4 A 200-400, 3 or 2.5-5, up to 4 A 2·4, 3 or 4 NA NA NA

times daily 4 times daily times daily times daily.c

C 100·200, 3 or C 200, 3 or 4 8, twice dailyd

4 times daily times daily ce

Premature labour NA NA NA 4,3 or 4 NA NA 10-45I1g/times daily for min'maintenance

a Can be repeated 4-hourly if required.b Injected slowly and repeated if necessary. For status asthmaticus, infusion rates of 3 to 20 IIg/min are generally adequate.c For non-responders this may be increased cautiously to a maximum of 8mg 4 times daily.d Controlled release tablet.e For children aged 6 to 11 years the recommended dosage is 2mg 3 or 4 times daily (up to a maximum of 24mg daily in divided

doses); for children aged 2 to 5 years the recommended dosage is 0.1 mg/kg 3 times daily (not to exceed 2mg 3 times daily),although for non-responders this may be increased to 0.2 mg/kg 3 times daily (not exceeding 4mg 3 times daily). For childrenaged 3 to 12 years controlled release tablet 4mg twice daily is also recommended.A starting rate of 10 IIg/min is recommended and this can be increased at 10-min intervals until the necessary response isobtained; maintenance can be achieved with oral therapy.

Abbreviations: A = adults; C = children; NA = not applicable.

Moreover, in many countries intravenous salbu­tamol is the standard emergency treatment for themanagement of severe acute asthma.

Inhaled salbutamol has been shown to be an ex­tremely effective agent in the prophylaxis of ex­ertional asthma, being at least as effective as ter­butaline and fenoterol, and superior to oralsalbutamol, sodium cromoglycate, methylxan­thines , atropine and ipratropium bromide.

Studies with salbutamol in children have shownit to be an effective bronchodilator, at least as ef­fective as all the commonly used Ih-agonists, anti­cholinergic agents and methylxanthine derivatives.

Since Ih-adrenoceptor agonist drugs producebronchodilation by a different mechanism fromother groups of bronchodilator drugs, it is reason­able to anticipate the possibility of improved re­sponse by combining such agents, at least in patientsin whom bronchodilation is less than maximal witha single agent. Indeed, in many studies, combina­tions of salbutamol with anticholinergic, antihist­amine drugs, methylxanthine derivatives, and in afew studies with beclomethasone dipropionate , wereoften more effective than individual drug therapy;however, some diverging results necessitate confir­mation of this apparent improved response to

Salbutamol: A Reappraisal

combination therapy in further well-designedstudies.

Surprisingly for such a well-established drug assalbutamol there are few reported long term stud­ies of its use, but in those that have been per­formed salbutamol was shown to be both effectiveand well tolerated in all forms of reversible ob­structive airways disease.

It is interesting to note that among the extra­pulmonary properties of salbutamol, which may beinterpreted as side effects during therapy, are anumber of actions which form the bases for sal­butamol use in other disease states. These includeits widespread and effective use for inhibition ofpremature labour, novel roles in the treatment offamilial hyperkalaemic periodic paralysis, and as aperipheral vasodilator in the treatment of cardiacfailure. However, further well-designed studies arerequired which should attempt to define moreclearly the patients in whom this type of therapywould be of benefit.

In conclusion , after many patient-years of suc­cessful clinical use salbutamol holds a prime po­sition in bronchodilator therapy. Newer agents,some with novel mechanisms of action, are beingstudied as alternative treatments in reversible ob­structive airways disease, but none at this stage havebeen shown to supersede salbutamol. Thus salbu­tamol remains a 'first-line' treatment for many ofthe bronchospastic diseases, and its future use seemsassured.

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Authors' address : Allan H. Price, ADIS Press Limited, 41 Cen­torian Drive, Private Bag, Mairangi Bay, Auckland 10, New Zea­land.