Aerosolized drugs can be used to provide both quick relief of respiratory difficulty and long-term treatment (Table Recommended Dosages for Aerosolized Medications in Horses). Quick relief can be provided by short-acting β2-adrenergic agonists or anticholinergic drugs. Long-term therapy is provided by use of antiinflammatory drugs and perhaps long-acting β2-adrenoceptor agonists.
Table Recommended Dosages for Aerosolized Medications in Horses
|Class||Active Ingredient||Formulation||Dosage||Manufacturer / Brand Name||Frequency|
|Corticosteroids||fluticasone propionate||44, 110, or 220 μg/ puff||2200 μg||Glaxo Wellcome / Flovent 220||Once to twice daily|
|beclomethasone dipropionate||HFA 40-80 μg/puff||500-1500 μg||3M Pharmaceuticals / QVAR||Once to twice daily|
|chlorofluorocarbon 42-84 M-g/puff||1500 M-g||Claxo Wellcome / Beclovent||Once to twice daily|
|Short-acting β2-agonists||albuterol (Salbutamol)||90 μg/puff||450-900 μg||Schering Corporation / Proventil||prn; not to exceed 4x/week unless in conjunction with corticosteroid|
|fenoterol||0.1 mg/puff||1-3 mg||Boehringer Ingelheim / Berotec||prn; not to exceed 4x/week unless in conjunction with corticosteroid|
|Long-acting β2-agonists||salmeterol||25μg||210 μg||Glaxo Wellcome / Serevent||Once to twice daily in conjunction with corticosteroid therapy|
|Mast cell stabilizers||sodium cromoglycate||800 μg||8-12 mg||Aventis Pharmaceuticals / Intal||Once to twice daily|
|nedocromil sodium||1.75 mg||17.5 mg||Aventis Pharmaceuticals / Tileade||Once to twice daily|
|Parasympatholytics||ipratropium bromide||20n.g||90-180 μg||3M Pharmaceuticals / Atrovent||2-4 x daily|
prn, As needed.
Short-Acting Bronchodilator Drugs
Short-acting p2-adrenoceptor agonists such as albuterol and fenoterol are vitally important in treatment of acute exacerbations of RAO. The horse that is laboring to breathe and has paroxysmal coughing will experience rapid relief with the use of β2-agonists. However, these are correctly termed rescue drugs and should not be used on a regular basis. Remembering that the inflammatory condition will persist despite apparent improvement because of transient bronchodilation and that the disease may worsen if other therapy is not administered concurrently is important. Regular use of p2-agonists in the absence of antiinflammatory medication may mask clinical signs that would otherwise indicate progressive worsening of the disease — in particular, further airway obstruction with mucus.
Short-acting p2-agonists are not performance-enhancing in humans, and increasing evidence supports this finding in horses. Nonetheless, albuterol and similar drugs remain proscribed by all equine sporting events, and due care should be taken to stop drug administration before competition. Short-acting β2-agonists can be useful in horses with inflammatory airway disease and underlying airway obstruction to improve the return to training. Administration of albuterol may also increase the peripheral lung deposition of other concurrently used drugs such as corticosteroids. Short-acting bronchodilators are also useful during lung function testing to assess the reversibility of airway obstruction in horses with RAO. Most horses bronchodilate in response to 450 μg of albuterol, irrespective of the delivery device (see “Aerosolized Drug Delivery Devices”).
Although aerosolized β2-agonists have a relatively low incidence of side effects, excessive use, or even standard use in sensitive individuals may result in systemic effects such as trembling, anxiety, and cardiac arrhythmias. This author has noted these signs in individuals treated with 900 μg of albuterol, whereas other individuals tolerate a higher dose. Repeated use of the drug tends to decrease side effects as the body down-regulates receptors. Very occasionally, horses may exhibit signs of bronchoconstriction with β2-agonists. This paradoxic response is transient — probably caused by the effects of the drug vehicle on airways.
In horses, bronchoconstriction is vagally mediated; thus parasympatholytic drugs are effective in mitigating bronchospasm. Ipratropium bromide is a quaternary derivative of atropine, and this formulation results in little systemic uptake. It antagonizes the acetylcholine receptor on bronchial smooth muscle, reduces release of calcium from intracellular stores, and causes airway smooth muscle relaxation. As with any parasympatholytic drug, potential for tachycardia, thickened mucus, decreased ciliary beat frequency, and decreased mucociliary clearance exists; however, studies in horses have showed no such side effects with doses up to 1200 micrograms. The index of safety is considerably greater than systemically administered atropine. Ipratropium has a slower onset of action than does albuterol, and its actions seem to be confined primarily to the central (larger) airways rather than bronchioles. Studies in horses suggest that pulmonary function begins to improve 15 minutes after administration. Although duration of action has only been verified through 1 hour, clinical evidence suggests that horses experience relief for up to 4 to 6 hours. Although ipratropium may act as a useful adjunct to p2-agonists for a rescue treatment during exacerbations of RAO, it is not the primary treatment of choice because of its slower onset of action. In horses with adverse responses to p2-agonists, ipratropium bromide may be preferred.
Corticosteroids remain the cornerstone of successful treatment for both inflammatory airway disease and RAO. Inhaled corticosteroids have truly revolutionized the treatment of recurrent airway obstruction and inflammatory airway disease. Although initial systemic tapered corticosteroid therapy is often necessary with all but very mild inflammatory airway disease, regular inhaled therapy is essential for long-term success in most cases. Inflammation underlies remodeling of the airways with accompanying airway hyperreactivity — or increased twitchiness of the airways — and consequent coughing and expiratory dyspnea. Bronchodilator drugs will help to relieve acute, debilitating bronchospasm, but only consistent anti-inflammatory therapy, in conjunction with avoidance of environmental triggers, will break the cycle of inflammation, airway hyperreactivity, and bronchoconstriction. This philosophy reflects the view that both inflammatory airway disease and recurrent airway obstruction are chronic diseases; although they are clinically episodic, the underlying pathology persists even when the disease appears to be quiescent. Hence consistent vigilance in countering airway inflammation is necessary. The most important factor in limiting regular use of inhaled corticosteroids is cost; drugs such as fluticasone and beclomethasone are very expensive.
The antiinflammatory effect of corticosteroids in both recurrent airway obstruction and inflammatory airway disease is impressive. Corticosteroids activate gluco-corticoid receptors, thus putting into motion a profound inhibition of the arachidonic acid cascade and limiting production of leukotrienes and other inflammatory molecules. Corticosteroids alter the transcription of genes such as inflammatory cytokines and enzymes, directly inhibit inflammatory cells, and decrease goblet cell hyperplasia. Thus they inhibit airway reactivity both by decreasing the mediators available to initiate bronchoconstriction and by preventing the development of airway thickening that geometrically enhances airway hyperreactivity. It has been shown in humans and animals that the efficacy of corticosteroids is limited with high levels of inflammation because transcription factors bind to glucocorticoid receptors, thus blocking the steroid interaction. Response to steroids can vary considerably from horse to horse.
Despite the success of systemic glucocorticoids in limiting airway inflammation, clinicians must aim to limit their use, as their side effects are both considerable and clinically important. Fluticasone propionate (FP) and beclomethasone dipropionate (BDP) are the two most potent, best studied, and most commonly used inhaled corticosteroids in both the horse and in man. They are considered second-generation drugs in that they have greater affinity for the glucocorticoid receptor, and their increased lipophilicity results in longer duration of action and less systemic absorption. In all, this greatly decreases the potential for systemic side effects and allows chronic use of these drugs. Studies in humans have shown that the longer the use of corticosteroids is delayed both in adults and in children, the worse subsequent lung function becomes. Indeed, regular use of inhaled corticosteroids in humans has been shown to be associated with a greatly reduced risk of death from acute exacerbations of asthma. As there are similarities in the nature of inflammation in horse (RAO) and human (asthma), many concepts in humans that pertain to steroid effects are worth noting.
RAO horses treated with beclomethasone dipropionate have shown both objective and subjective evidence of decreased airway obstruction as well as decreased pulmonary neutrophilia within 24 hours of initiation of therapy. Doses range from 500 micrograms to 1200 micrograms with the hydrofluoroalkane (hydrofluoroalkane-134a) formulation, which is approximately half the recommended dose when using the chlorofluorocarbon formulation (see “Aerosolized Drug Delivery Devices”). Newer formulations of beclomethasone dipropionate that incorporate hypothalamic-pituitary axis (HPA) as the propellant have more uniform particle size, are more uniformly mixed, and require little to no agitation or waiting before actuation of the inhaler. Although evidence of adrenal/hypopituitary axis (HPA) suppression (i.e., reduced serum cortisol levels) with all doses more than 500 mg exists, this does not appear to pose a risk of chronic HPA suppression or rebound Addisonian crisis. Fluticasone propionate decreases pulmonary neutrophilia, improves pulmonary function, and reduces airway hyperreactivity in RAO-affected horses. Fluticasone propionate is the most potent of the inhaled corticosteroids, has the longest pulmonary residence time, and causes the least adrenal suppression.
The general strategy pursued at the pulmonary clinic at Tufts University School of Veterinary Medicine in Med-ford, Mass., is to treat in a stepwise manner, starting with a high dose given frequently and gradually reducing therapy until the lowest effective dose can be found. If owners are vigilant in environmental control and are compliant with treatment recommendations, many horses can eventually be treated successfully on an every-other-day basis to prevent recurrences. Some owners have been successful in documenting seasonal exacerbations; in this case we recommend beginning treatment with inhaled corticosteroids — and, occasionally, mast cell inhibitors — at least two weeks before the anticipated allergen season. It is important to remember, however, that unless all stimuli for pulmonary inflammation are removed, the effect of inhaled corticosteroids is transient, and signs will return when the horse is exposed to organic dust and other allergens. Corticosteroids should not be used for quick relief or for rescue therapy because the onset of action is at least 24 hours, and several months of regular use may be necessary for optimal results. With severe inflammation, systemic corticosteroids are usually necessary to achieve breakthrough before inhaled therapy is initiated. Most horses with recurrent airway obstruction and inflammatory airway disease will require loading doses for 2 to 4 weeks of systemic steroids before reliance on aerosol medications, although trials to demonstrate the effective preventive dose are lacking.
Mast Cell Inhibitors
Mast cells are important mediators of inflammation in horses with inflammatory airway disease or RAO, with studies linking mast cells with airway reactivity, environment, and levels of inflammatory mediators in lavage (bronchoalveolar lavage) fluid. Sodium cromoglycate has had the most extensive use in horses and is one of the few aerosolized medications that has been examined in the horse. More recently, nedocromil sodium, which has a longer duration of action and appears to be more potent in humans, has been used clinically in horses. These drugs, which most likely work by inhibiting chloride channels, act to stabilize the mast cell membrane, thus blocking degranulation and inhibiting the allergic response at an early stage. Early workers showed that clinical signs were greatly attenuated and that lung function was mildly improved in horses with recurrent airway obstruction that were given sodium cromoglycate before challenge. Other studies indicate that disodium cromoglycate can decrease the amount of histamine in mast cells that are seen in the bronchoalveolar lavage of a subset of horses with inflammatory airway disease. In our hands, disodium cromoglycate and nedocromil sodium appear to be beneficial in some horses with airway hyperreactivity and increased percentages of mast cells. These drugs have a tendency to cause cough, and horses do not like them, perhaps because of a bad taste. Anecdotal evidence suggests that pretreatment with albuterol may attenuate some of the cough response.
The greatest therapeutic effect is seen when this class of drug is given as a long-term therapy and before exposure to allergens — such as before allergy season or before transporting a horse to a new environment. Understandably, this involves less customer satisfaction and consequently poorer compliance with drugs that do not have a visibly dramatic effect, such as the β2-agonists and even the potent corticosteroids.
Shifting paradigms about nonseptic airway disease in the horse that emphasize inflammation have also led to new approaches to treatment. Initially, this meant that β2-agonists were relegated strictly to treatment of acute exacerbations or for initial bronchodilation while systemic and inhaled steroids were taking effect. This author tended to counsel against regular use of β2-agonist drugs except in moderate to severe RAO. However, following the asthma model, the author has begun to treat selected cases of recurrent airway obstruction and moderate inflammatory airway disease with long-acting p2-agonist therapy in addition to inhaled corticosteroids, with the initial impression of enhanced performance and quality of life. It cannot be emphasized enough, however, that regular use of long-acting β2-agonists must be accompanied with regular use of inhaled corticosteroids.
Although the most obvious and important effect of β2-agonist agents is bronchodilation, they have a host of other actions that may, in conjunction with antiinflammatory therapy, actually benefit the animal with inflammation-associated airway dysfunction. β2-agonists have been found — in humans and animals — to inhibit smooth muscle proliferation; increase the force of contraction of the diaphragm and intercostals muscles; act as mild anti-inflammatories by decreasing neutrophil numbers, activity, and ability to release cytokines; protect the epithelium against microorganisms by maintaining cyclic adenosine monophosphate (cAMP) levels; improve mucociliary clearance by increasing ciliary beat frequency; and even enhance surfactant secretion. Studies in asthmatics and humans with chronic obstructive pulmonary disease indicate that the addition of long-acting β2-agonists, in conjunction with corticosteroid therapy, allow a decrease in the corticosteroid dose (which can decrease cost of treatment considerably), decrease frequency and severity of asthma exacerbations, and improve pulmonary function parameters. When long-acting B2-agonists were used regularly in asthmatic children in the absence of corticosteroid therapy, airway hyperreactivity was not reduced, and symptoms were not adequately controlled.
The most commonly used long-acting B2-agonists are salmeterol and formoterol, whose basic mechanism of action is the familiar cAMP pathway. Salmeterol has specific binding to the B2-adrenoreceptor because of its molecular modifications and repeatedly stimulates the receptor. In this way it has a long, concentration-independent duration of action. Its Iipophilicity results in slow onset of action; thus it should not be used when rapid bronchodilation is desired. Its duration of action in horses is 6 to 8 hours. Formoterol — although also lipophilic — achieves its long life by being retained as a depot and is thus concentration-dependent. Formoterol has the property of being able to reach the receptor by the aqueous phase and thus has a much more rapid onset of action than salmeterol in humans; formoterol pharmacokinetics have not been studied in horses. Although the duration of action in humans appears to be at least 12 hours, horses appear to experience maximum relief for only 6 hours.