Inhalation Therapy of Airway Disease
The current approach to management of inflammatory airway disease is through inhalation therapy with nebulizers or metered-dose inhalers (MDIs). With inhalation therapy, high drug concentrations are delivered directly to the lungs via nebulizers or MDIs, and systemic adverse effects are avoided or minimized. The onset of action for inhaled bronchodilators and anti-inflammatory drugs is substantially shorter than that of oral or parenteral formulations. Nebulizers have long been used in animals, but the overall efficiency of drug delivery is low, and the equipment is cumbersome and inconvenient for owners. Administration of medications via MDIs is commonplace in treatment of human asthma and seems to benefit management of animals as well. Human MDIs are designed to provide optimal lung delivery after actuation during a slow, deep inhalation. However, this is impossible to control in animals. The addition of spacers enables MDIs to be used in animals. Spacers decrease the amount of drug deposited in the oropharynx (up to 80% of the actuated dose with the MDI alone), thereby reducing systemic drug absorption. Drugs available in MDI formulations include β2-agonists, glucocorticoids, ipratropium bromide, cromolyn sodium, and nedocromil. Each product delivers a set amount of drug per actuation (puff). In the USA, MDIs are labeled according to the amount of drug delivered at the mouthpiece, whereas in Canada and the EU they are labeled according to the amount of drug delivered from the valve. MDIs are color-coded to aid identification. Even in human medicine, the relative potencies, risks of adverse effects, and optimal dose of the different inhaled asthma medications remain unclear. Unfortunately, some drugs that would be useful in veterinary patients are not available in MDIs; dry powder inhalers are not suitable for use in animals. Clinical use of MDI medications in asthmatic cats, dogs with chronic bronchitis, and horses with recurrent airway obstruction is promising but mostly anecdotal, and clinical trials are needed to determine the most efficacious therapies.
MDIs (eg, OptiChamber™, AeroChamber®) used in humna patients may be modified for use in dogs and cats, and small animal–specific spacers are available (eg, AeroKat™, AeroDawg™, Feline Breathe Easy™, Nebulair™). The OptiChamber™ must be modified with a suitable face mask, such as the type used to “mask” cats for anesthesia. The AeroChamber is available with a variety of face masks intended for infants, children, and adults that will conform to a variety of veterinary patients. The Nebulair and Feline Breathe Easy spacers are valveless, so the actuation must occur with the mask applied to the face of the animal. The AeroKat and AeroDawg are equipped with “flapper” valves so the dog or cat can be visualized breathing in the medication. MDIs were originally used in horses via the Aeromask™, but the mask is bulky and rather expensive. The Aerohippus™ is similar to the AeroKat and AeroDawg, with a large, bell-shaped cone that fits over a horse’s nostril. It also has a valve indicator.
Short-acting β2-agonists such as albuterol (salbutamol) in MDIs are the medications of choice to treat acute exacerbations of bronchoconstriction, because they relax smooth muscle and promptly increase airflow. Although effective for symptomatic relief, β2-agonists do not control inflammation. Airway obstruction may persist despite appropriate use of inhalant bronchodilators because of bronchial wall edema and airway mucus plugging. In general, β2-agonists are extremely safe for use in animals when used as needed for bronchoconstriction. Toxicity typically requires a large overdose, such as when dogs chew on and puncture the inhaler, receiving a very large dose at one time (there are 200 doses in an albuterol/salbutamol inhaler). Massive overdose may induce severe tachycardia and hypokalemia, which, in turn, lead to extreme weakness, incoordination, and potentially cardiac standstill. Other less serious signs include dilated pupils, severe agitation and hyperactivity, hypertension, and vomiting.
Albuterol (salbutamol) is the medication of choice in all species for inhalation therapy of acute airway obstruction. It relaxes smooth muscle and increases airflow within minutes of administration; effects last 3–6 hr. Although effective for symptomatic relief, the β2-agonists do not control inflammation, and monotherapy may exacerbate asthma and increase morbidity and mortality. Racemic albuterol (R, S albuterol) is the most commonly prescribed short-acting β2-agonist and is composed of a 1:1 mixture of (R)-albuterol (the R-enantiomer) and (S)-albuterol (the S-enantiomer). The R-enantiomer has bronchodilatory and anti-inflammatory effects, and the S-enantiomer paradoxically is associated with increased airway hyperreactivity and pro-inflammatory effects. The paradoxical exacerbation of asthma with regular use of inhaled racemic albuterol in people is thought to be linked to preferential accumulation of S-albuterol in the lung, which has a much slower metabolism than R-albuterol. Neutrophilic airway inflammation in healthy cats was induced when receiving treatment with albuterol containing the S-enantiomer. These data suggest that the form of albuterol commonly prescribed to asthmatic cats can actually cause inflammation in “healthy” cats without preexisting airway disease. The S-enantiomer also exacerbates eosinophilic airway inflammation in experimentally asthmatic cats. This increase in airway inflammation associated with use of albuterol can be attenuated by concurrent use of glucocorticoids. Proper control of the underlying inflammation should reduce albuterol use to an as-needed only basis. One actuation (100 mcg Canada; 90 mcg USA) of albuterol can be administered for relief of bronchoconstriction as needed until clinical signs resolve.
Salmeterol is a long-acting β2-agonist; its onset of action is slow (15–30 min), but its duration of action is >12 hr. The long duration of action is due to diffusion into the plasma membrane of the pulmonary cells followed by slow release from the cells to interact with β2 receptors. It is not recommended for use in acute bronchoconstriction, but daily use with glucocorticoids provides better control of symptoms than simply increasing the glucocorticoid dose. It is not available in an MDI in all countries, and the dry powder inhaler is not suitable for animal use.
Other β2-agonists that may be available in MDIs include isoproterenol, fenoterol, formoterol, and terbutaline. Isoproterenol was commonly used to treat asthma before the more widespread use of albuterol, which has more selective effects on the airways. In Europe, an epidemic of deaths due to cardiotoxicity from overuse of isoproterenol inhalers led to withdrawal of the products. North American products have clear warning labels regarding the potential toxicity.
Inhaled glucocorticoids are the most potent inhaled anti-inflammatory drugs available. In people, early intervention with inhaled glucocorticoids improves asthma control, normalizes lung function, and may prevent irreversible airway damage. The potential risk of adverse effects is well balanced by their efficacy in management of chronic inflammation. Oral candidiasis (thrush), dysphonia, and reflex cough and bronchospasm are the most common adverse effects in people; all of these effects are reduced by use of a spacer. The risk of systemic adverse effects, such as suppression of the hypothalamic-pituitary axis, is less than with oral prednisone therapy. Inhaled glucocorticoid formulations include fluticasone, beclomethasone, flunisolide, and triamcinolone. Currently, fluticasone is considered the most potent formulation with the longest duration of action and is the most commonly used inhaled glucocorticoid in veterinary patients.
Ipratropium bromide is a quaternary derivative of atropine that lacks its adverse effects and is available in an MDI (500 mcg/actuation), alone or in combination with albuterol. In people with asthma, ipratropium bromide is used as an additional reliever medication to reverse bronchoconstriction when inhaled short-acting β2-agonists do not provide enough relief. Its anticholinergic action also decreases mucous secretions. In an experimental model of feline asthma, longterm antigen sensitization caused an augmented muscarinic receptor response to acetylcholine. Modulation of muscarinic receptors with anticholinergic drugs may be useful to treat asthmatic cats. Ipratropium has shown efficacy for recurrent airway obstruction in horses. It is not well absorbed after inhalation, so it does not cause systemic anticholinergic effects.
Cromolyn sodium and nedocromil sodium are chloride-channel blockers that modulate mast cell–mediator release and eosinophil recruitment. They are both available in MDIs. Cromolyn sodium and nedocromil sodium have strong human safety profiles, but nedocromil sodium has been reported to have a broader spectrum of efficacy. In people, the clinical response to these drugs is less predictable than the response to glucocorticoids. There are no published reports of the use of cromolyn or nedocromil in asthmatic cats or dogs with bronchitis; however, pretreatment with nedocromil sodium aerosols attenuated viral-induced airway inflammation in Beagle puppies. Further investigation of these drugs in asthmatic cats seems warranted given the sensitivity of this species to serotonin released from degranulating mast cells.
Lidocaine, commonly used as a local anesthetic and antiarrhythmic agent, is used as a steroid-sparing treatment in human asthma. Initially used topically to prevent cough during bronchoscopic procedures, lidocaine, administered via nebulization, is effective for intractable cough and asthma by inhibition of eosinophil-active cytokines. Nebulization provides direct drug delivery to the lung, with minimal systemic drug absorption and few adverse effects. Nebulized lidocaine reduced airway hyperresponsiveness in experimentally asthmatic cats but did not affect airway eosinophilia, so it probably should be combined with glucocorticoids in management of feline asthma.
For emergency management of dyspnea in cats and dogs, 2–4 puffs of albuterol should be given every 5 min until clinical signs resolve. Additional therapy may include oxygen and an IV dose of a rapid-acting glucocorticoid.
Current recommendations for therapy of feline asthma and canine bronchitis are to use albuterol only as needed for bronchodilation and fluticasone bid. For initial therapy of moderately affected animals, a 5-day course of oral prednisone (or prednisolone) at 1 mg/kg may be helpful. Severely affected animals may require 1 mg/kg of prednisone (or prednisolone) every other day. Adjunctive therapy with other inhaled or orally administered anti-inflammatories and bronchodilators may be useful in some animals. Therapy must be individualized for each animal.
For horses with recurrent airway obstruction, environmental management and a combination of bronchodilator and anti-inflammatory therapy is recommended. Current recommendations are to use 500 mcg of albuterol every 2 hr as needed and fluticasone at 2–4 mcg/kg bid. Beclomethasone has also been used at 1–3 mcg/kg, bid, but it causes more adrenal suppression in horses than fluticasone at these doses.