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Therapeutic Aerosols 2-Drugs Available by the Inhaled Route

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Therapeutic Aerosols 2-Drugs Available by the Inhaled Route Thorax 1984;39:1-7 Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from Editorial Therapeutic aerosols 2-Drugs available by the inhaled route Inhalation treatment can be said to have stood the umes have been written about them and their test of time, since records can be traced back several administration.3 Reiterating most of this would be thousand years. In ancient Greece, Hippocrates like taking "coals to Newcastle" for the readers of employed the inhalation of vapours distilled in a pot, Thorax and therefore only selected aspects will be the lid of which was pierced by a reed;' sulphur and mentioned. arsenic were said to have been used. The patient The naturally occurring catecholamine adrenaline breathing these hot vapours needed protection with was the earliest of these drugs to be given by inhala- moistened sponges to avoid scalding. The popularity tion,4 followed by isoprenaline (isopropylnoradren- of these inhalation procedures has waxed and aline) in about 1960. Since adrenaline, however, waned, as Miller' writes-at times they have been stimulates both a and ,3 receptors in the heart and over praised and unwisely used, and at other times periphery and isoprenaline stimulates 8,/ and (2 unreasonably condemned and virtually abandoned. receptors, both drugs may give rise to undesirable The latter phrase still applies to some extent today. cardiovascular side effects such as tachycardia or Until the middle of the present century, inhalation arrhythmias. Adrenaline, whether given by injection treatment with volatile aromatic substances with a or by inhalation, is now little used in Britain. It is, mild irritant action such as menthol, thymol, and however, still given by injection for acute asthma in eucalyptus and smokes derived from burning vari- young patients and it is still available on prescription copyright. ous types of plant leaf, notably Atropa belladonna for use in an MDI or in a hand held "squeeze bulb" and Datura strammonium, was quite commonly inhaler in a mixture that also contains atropine recommended for disorders of the upper and lower methonitrate and papaverine hydrochloride (Bro- airways. Several present day pharmaceuticals used von). Furthermore, MDIs containing adrenaline are for respiratory treatment have been derived from freely available over the counter in the United http://thorax.bmj.com/ ancient remedies2-for example, khellin was the States. predecessor of cromoglycate, while burning Datura Chemical manipulation of the side chains of the strammonium leaves form the basis of the asthma adrenaline and isoprenaline molecules has led to the cigarette, which is still available from herbalists. development of sympathomimetic drugs possessing These substances have been largely replaced by a more selective action on respiratory f2 receptors. the range of modern pharmaceuticals available for Salbutamol, terbutaline, and fenoterol are the best inhalation either from a metered dose inhaler known of these compounds, but at least 14 related (MDI), dry powder inhaler, or nebuliser or for the drugs have been described.5 While cardiovascular nose by nasal spray. Although the MDI is the most side effects are much reduced, skeletal muscle tre- on September 25, 2021 by guest. Protected popular method of administering bronchodilator mor and cramps are occasionally noted, even with and corticosteroid aerosols, the nebuliser has the the small doses taken by inhalation. One potential great merit of flexibility-virtually any drug solution drawback of treatment with f8 agonists is a fall in or suspension can be nebulised. Most drugs are arterial oxygen tension owing to a transient worsen- inhaled for topical treatment of the upper and lower ing of ventilation:perfusion ratios.6 This is seen par- respiratory tract, but some may also be given as ticularly in severe acute asthma, where hypoxaemia aerosols for their systemic effect. may already be substantial. The potential effect on the heart of increasing hypoxaemia must be consi- Beta agonists dered. Supplemental oxygen treatment should, however, readily relieve this hypoxaemia.' Although Beta agonists are undoubtedly the most common early experience with isoprenaline suggested that /8 type of drug given by inhalation from an MDI. Vol- agonists might be inherently short acting, the selec- tive f2 agonists have been shown to be active for up Address for reprint requests: Dr SW Clarke, Department of to seven hours.8 Thoracic Medicine, Royal Free Hospital, London NW3 2QG. In Britain /8 agonists given by inhalation are the Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from 2 standard first line of treatment in asthma and butamol from an MDI is usually 200 gg, of which chronic obstructive airways disease, in which they about 10% or 20 ,mg will be deposited within the may be used on demand for relief of symptoms as bronchial tree'8'9 and stimulate ,8 receptors. By con- they arise or as regular maintenance treatment to trast, the nebulised dose is usually 5 mg in 1 ml avert symptoms. Their preventive effect is particu- (diluted with, say, 3 ml of saline). Of this 5 mg, 10% larly well seen in the suppression of exercise induced or 500 ,ug will reach the lungs,2' 25 times more than asthma.9 Inhaled treatment with /8 agonists alone the lung dose achieved with the MDI. Nevertheless, may control mild asthma. Combined with cromo- if the effect of dose is taken into account by the glycate they will control symptoms in most patients construction of dose response curves it is found that with extrinsic asthma and combined with inhaled the curves achieved with MDI and nebuliser are corticosteroids in most patients with intrinsic almost identical.22 A lung dose of only 30 ,ug asthma. Given in sufficient dosage an inhaled, fenoterol delivered by nebuliser has been shown to agonist may control attacks of severe acute asthma. cause maximal bronchodilatation in a group of Sometimes this is given in conjunction with par- asthmatics with FEV,s ranging from 27% to 78% of enteral /3 agonists or methyl xanthines and usually the normal predicted value.23 Arguably an increase treatment is supplemented by systemic cortico- in the dose from a nebuliser might be beneficial if steroids. Nebulised salbutamol has been particularly the degree of bronchoconstriction is severe and the successful in the treatment of children in hospital number of ,3 receptors to be stimulated is increased. with severe acute asthmatic attacks,'0 but its Fears that the large doses of 8 agonist convention- domiciliary use in such cases needs to be carefully ally given by nebuliser may be harmful are probably supervised and help must be sought early if there is a unfounded, although whether these doses are usu- poor response." ally required is another matter and needs further Beta agonists have the useful merit of increasing investigation. the rate of mucociliary clearance, which is known to be abnormally slow in many patients with obstruc- Other bronchodilators tive airways disease.'2 Studies of the effect on clear- copyright. ance of aerosolised 83 agonists, however, have not ANTICHOLINERGIC DRUGS reached unanimous conclusions. Improvement of Anticholinergic drugs act by blocking the muscarinic clearance has been demonstrated after the adminis- action of acetylcholine. Atropine is an effective tration of adrenaline and isoprenaline," sal- bronchodilator and has been used for many years butamol,'4 and orciprenaline,'9 although the doses but it has the undesirable side effect of drying airway http://thorax.bmj.com/ used were larger than those usually required for secretions. It may also precipitate glaucoma and in bronchodilatation. In clinical practice patients often men it may induce urinary retention. The synthetic remark on improved expectoration after inhaling anticholinergic agent ipratropium bromide appears these drugs, though bronchodilatation alone may to be free from these side effects in the doses nor- improve coughing efficiency. mally delivered.24 It is an effective bronchodilator at One feature of treatment with ,3 agonists which is a dose one tenth of that required to inhibit saliva insufficiently appreciated is the wide variation in the production and one fiftieth of that causing tachycar- dose administered by the various routes. It should dia.3 It has a slightly slower onset of action than the be noted that the small dose of drug reaching the ,8 agonists but its duration of action is similar. Ipra- on September 25, 2021 by guest. Protected lungs and activating /8 receptors is responsible for tropium bromide delivered by nebuliser has been most of the bronchodilator effect'6 and the cardio- used successfully to control acute asthma,25 though vascular side effects.'" Absorption of drug into the here it is unlikely to supplant the ,8 agonists. In some systemic circulation via the lung may also play a bronchitic patients with airways obstruction ipra- part.'8 Most of the dose from an MDI is deposited in tropium may give dramatic relief, but occasionally the oropharynx.'9 Some of this may be absorbed paradoxical bronchoconstriction is noted.26 When through the buccal mucosa,20 though most is swal- ipratropium is given in conjunction with a ,8 agonist lowed and converted to an inactive metabolite dur- additional bronchodilatation may be achieved,27 ing its passage through the wall of the intestine or although the extent of this varies from patient to the liver.'8 About 75% (and in the case of iso- patient.28 It has been suggested that ipratropium and prenaline 90%) of the oral dose is converted, so that the ,B agonists may act preferentially on different the required oral dose is typically greater than the parts of the bronchial tree, but the evidence has inhaled dose by a factor of 10. With the nebuliser been conflicting. Some studies have shown that anti- most of the non-inhaled drug is retained within the cholinergic agents act on large conducting airways device itself.2' and / agonists on small airways;2930 others suggest To give an example, the inhaled dose of sal- that ipratropium is equally effective in both large 3 Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984.
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