Drug Therapy for Equine Asthma – Bronchodilators

Bronchodilators, as with corticosteroids, can be administered both systemically and via aerosol, however, aerosolization is by far the preferred method. Both beta-2 agonists (B2-ARs) (sympathomimetics) and parasympatholytics are used in horses. Of the B2-ARs commonly used in equine medicine, albuterol, which is known as salbutamol everywhere but in the U.S., is primarily administered by inhalation, and clenbuterol is administered orally. For the parasympatholytic agents ipratropium is administered by inhalation and atropine and N-butylscopolamine (Buscopan) are administered parenterally.

 

Although N-butylscopolammonium bromide can be used for rapid relief of bronchospasm, its effect is only short lasting. (Couetil 2012) The only longer lasting systemically administered bronchodilator is clenbuterol, a B2-AR that was approved for use in horses in the U.S. in 1998 under the brand name Ventipulmin® (Boehringer Ingelheim Vetmedica, Inc, St Joseph, MO). Severe toxicities have occurred when improperly compounded clenbuterol was administered to horses. The safety and efficacy of chronic administration of clenbuterol is controversial. Chronic administration of clenbuterol at 2.4 µg/kg (5 days on, 2 days off, for 8 weeks) was reported to have a negative impact on aerobic performance in horses. {Kearns 2002} Tachyphylaxis also appears to be a problem with chronic administration of clenbuterol. For example, a recent study demonstrated that after 3 weeks of clenbuterol administration at 0.8 µg/kg bwt PO, q12 hr increased airway reactivity was evident and the horses were refractory to the bronchodilatory effects of clenbuterol. (Nolen-Walston)

 

Most horses appear to tolerate the lower doses of clenbuterol well, but with higher doses horses may have tremors, tachycardia, sweating, and an appearance of anxiousness, among other signs. Together, these findings suggest that the practice of administering clenbuterol to horses in order to enhance performance is probably misguided at best, and harmful at worst. It is also important to recognize that the recommended duration of treatment is 30 days. Clenbuterol’s best use is as a short-term bronchodilator in horses that cannot tolerate aerosolized devices. Clenbuterol is not appropriate and should not be used as a chronic therapy.

 

Inhaled bronchodilators:

Albuterol is commonly used to elicit bronchodilation in IAD. It is important to remember that the inflammatory condition will persist despite apparent improvement due to transient bronchodilation, and the disease will worsen if the other two legs of treatment – corticosteroid (anti-inflammatory) therapy and avoidance of environmental triggers – are not pursued. Regular use of B2 agonists in the absence of anti-inflammatory medication may mask symptoms that would otherwise indicate progressive worsening of the disease, in particular further airway obstruction with mucus. Albuterol is the most affordable of the short-acting B2 agonists, however, levalbuterol, the R-enantiomer of albuterol, has recently become more affordable (trade name Xopenex). There is a possibility that albuterol may cause unexpected bronchoconstriction due to action of the L-enantiomer. Levalbuterol may prevent this, but paradoxical bronchoconstriction has occurred even with the use of lavalbuterol. Although regular use of inhaled albuterol for 10 days does not result in tachyphylaxis, it may be that longer use would result in treatment failure.

 

The preponderance of evidence shows that short-acting B2 agonists are not performance enhancing in humans, and there is little evidence to indicate that they are performance-enhancing in horses, (EVJ Suppl 1999, Bailey J effect of inhaled B2 AR) with one study showing a small increase in aerobic performance in Thoroughbred horses in a treadmill study, while the other failed to show any effect of albuterol administration on aerobic performance in Standardbreds on a treadmill. (Mazan 2001 AJVR)Nonetheless, all equine sporting events ban albuterol, and due care should be taken to stop drug administration before competition, noting that albuterol can be detected in urine for at least 48 hours after administration via metered dose inhaler. A recent study showed that budesonide is found in greater concentrations systemically when it is inhaled during exercise (an interesting concept), likely reflecting the depth of breathing, so this should be taken into account when determining withdrawal times. (Barton AK 2017) Short-acting B2 agonists can be useful in horses with a cough due to bronchoconstriction to improve the return to training. No more than 450 mg of albuterol by inhalation is necessary to bronchodilate most horses, irrespective of the delivery device chosen.

 

Although aerosolized B2 agonists have a relatively low incidence of side effects, excessive use or sensitive individuals may experience systemic effects such as trembling, anxiety and cardiac arrhythmias. The author has noted all these in individuals treated with 900 micrograms of albuterol, whereas other individuals show no signs of intolerance. Repeated use of the drug tends to decrease side effects as the body down regulates receptors.

 

Long-acting Inhaled B2-ARs therapy: We occasionally treat moderate IAD with long-acting B2-ARs 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 B2-ARs must be accompanied with regular use of inhaled corticosteroids. The most commonly used long-acting B2-ARs are salmeterol and formoterol, whose basic mechanism of action is the familiar cAMP pathway.   Their duration of action in horses is 6-8 hours.

 

Inhaled parasympatholytic therapy: The most commonly used inhaled parasympatholytic drug is ipratropium, a quaternary ammonium derivative of atropine; which produces bronchodilation lasting approximately 6 hours, which is at least 2 hours longer than albuterol. Although adverse side effects such as thickened mucus, tachycardia, and decreased ciliary beat frequency are possible with parasympatholytics, no such side effects have been reported in horses up to a dose of 1200 µg. Ipratropium cannot be considered a rescue drug, unlike atropine, because it has much longer onset of action; however, the effect may last somewhat longer than atropine. It is unusual for ipratropium to be necessary in IAD.

 

Mast cell stabilizers: These agents are cromones that block calcium channels preventing the release of histamine and tryptase, and the subsequent downstream cascade of prostaglandin and leukotriene formulation that eventually cause bronchoconstriction. Sodium cromoglycate can be efficacious in treating known mast cell mediated IAD, but will not be of use for treating the majority of horses with neutrophil-mediated disease. Their use, however, requires considerable owner compliance, as the maximum response to this drug occurs at 1-2 weeks after beginning treatment.

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