Bronchodilators are used in heaves-affected horses to relieve the obstruction of the small airways caused by airway smooth muscle contraction (see Table Medications Recommended for the Treatment of Heaves). Bronchodilator administration should be combined with strict environmental dust control and corticosteroid administration because inflammation of the lower airways may progress despite the improvement of clinical signs observed with drugs. Because of their rapid onset of action, bronchodilators are particularly helpful when immediate relief of clinical signs is required. The administration of bronchodilators to heavey horses may worsen hypoxemia, before an elevation in PaO2 values is observed. Although this rarely appears to lead to clinical problems, combining inhaled bronchodilators with intranasal O2 insufflation in horses with respiratory distress may be advisable. The agents most commonly used for bronchodilation in horses are β2-adrenergic agonists and xanthine derivatives.
Clenbuterol (Ventipulmin), a β2-adrenergic agonist, has bronchodilator effects and increases mucociliary transport. Side effects such as tachycardia and sweating rarely are seen with lower oral doses but are more frequent with intravenous administration. The clinical efficacy of clenbuterol at the lower recommended dosage (0.8 μg/kg q12h) in horses with heaves is inconsistent, if exposure to dusty hay and bedding is maintained. With higher dosages (up to 3.2 fig/kg) the efficacy of clenbuterol improves, but so does the frequency and severity of the side effects. Fenoterol, albuterol, pirbuterol, and salmeterol are other p2-agonist agents with potent bronchodilator effects that can be administered by inhalation. With inhaled β2-agonist agents, bronchodilation is rapid and side effects are minimal but, with the exception of salmeterol, beneficial effects are short lived and therefore require frequent drug administration.
Because of their potentially severe side effects, anti-cholinergic drugs generally are not administered systemically for the treatment of heaves. Ipratropium bromide can be administered safely by aerosol, but its effects are short lived. The use of sympathomimetic agents such as ephedrine, which stimulate both a and p receptors, has decreased because of the availability of more specific β2-adrenergic agonists.
Aminophylline (Cyanamid) and pentoxifylline are methylxanthine derivatives with nonspecific phosphodiesterase inhibitory properties. Phosphodiesterase (PDE) is a family of enzymes that catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and thereby terminates their role as second messengers in mediating cellular responses to various hormones and neurotransmitters. Activation of cAMP PDE may be a common mechanism to facilitate proinflammatory effects of cytokines and other proliferative agents. Aminophylline is used primarily as a bronchodilator in horses, but it also enhances mucociliary clearance, respiratory drive, and contractility of the diaphragm and modulates immune function. Side effects such as excitability, tachycardia, muscular tremors, and sweating are commonly observed. Because of their low therapeutic index, the use of aminophylline and other salts of theophylline are commonly preferred.
Pentoxifylline currently is approved in some countries for the treatment for navicular disease in horses. It also has bronchodilating properties, inhibits neutrophil recruitment to inflammatory sites, and at high concentration is a potent inhibitor of tumor necrosis factor (TNF)-α production. High dosage of pentoxifylline (16 g/horse, q12h) has been shown to be as beneficial as atropine for the relief of airway obstruction. However, oral absorption is variable and the efficacy of more practical lower dosages should be assessed.
Selective PDE inhibitors, particularly of the PDE4 subtypes, have been studied for the treatment of lower inflammatory airway diseases in people owing to the expression of PDE4 in airway smooth muscle, pulmonary nerves, and almost all inflammatory and immune cells relevant to the pathogenesis of asthma. A selective PDE4 inhibitor is effective at inhibiting the ex vivo production of inflammatory mediators by equine leukocytes but fails to be effective for the treatment of horses affected with heaves.
Of the various mediators known to be involved in lung inflammatory diseases, leukotrienes are considered to be among the most important. Leukotrienes are metabolites of the arachidonic acid produced via the 5-lipoxygenase (5-LO) enzyme and its essential cofactor, the 5 lipoxygen-ase-activating-proteins (FLAP). Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent bronchoconstrictors that also increase the airway vascular permeability and mucus production. However, inhibition of leukotriene synthesis or antagonists of LTD4 receptors is not effective for the treatment of heaves.