Systemic Therapy of Inflammatory Airway Disease
The β-adrenergic receptor agonists have beneficial effects in treatment of bronchoconstrictive respiratory tract diseases (see Table: β-Adrenergic Receptor Agonist Drugs). Bronchial smooth muscle is innervated by β2-adrenergic receptors. Stimulation of these receptors leads to increased activity of the enzyme adenylate cyclase, increased cAMP, and relaxation of bronchial smooth muscle. Stimulation of β receptors on mast cells decreases the release of inflammatory mediators from mast cells, but other inflammatory cells are not suppressed. There is some evidence that β-adrenergic receptor agonists increase mucociliary clearance in the respiratory tract. The β-adrenergic receptor agonists should be used with caution in animals with preexisting cardiac disease, diabetes mellitus, hyperthyroidism, hypertension, or seizure disorders, or that are being treated with digoxin, tricyclic antidepressants, or monoamine oxidase inhibitors.
β-Adrenergic Receptor Agonist Drugs
Epinephrine (adrenaline) stimulates α and β receptors, resulting in pronounced vasopressive and cardiac effects in addition to bronchodilation. Epinephrine is reserved for emergency treatment of life-threatening bronchoconstriction (eg, anaphylaxis). The nonspecific stimulation of other receptors and its short duration of action make it unsuitable for longterm use. Epinephrine is available as a 1 mg/mL solution. Its onset of action is immediate, and the duration of effect is 1–3 hr.
Isoproterenol is a potent β-receptor agonist. It is selective for β receptors, but cardiac (β1) effects make it unsuitable for longterm use. It is administered by inhalation or injection and has a short duration of action (<1 hr). For emergency relief of bronchoconstriction in horses, it is given by slow IV solution at a dilution of 0.2 mg/50 mL of saline. Administration is discontinued when the heart rate doubles.
Terbutaline is a β2-receptor agonist similar to isoproterenol but longer acting (6–8 hr). It may be available in some countries as an injectable solution, powder inhaler, or oral syrup and tablets. For cats with feline asthma that experience frequent, severe bronchoconstrictive episodes despite chronic glucocorticoid therapy, injectable terbutaline can be dispensed to owners with instructions to administer 0.01 mg/kg, SC, to treat episodes of bronchoconstriction at home. An increase in the cat’s heart rate to 240 bpm and a 50% decrease in respiratory rate indicates a positive effect. Terbutaline also can be given as chronic oral therapy at 0.625 mg/cat, bid (¼ of a 2.5-mg tablet). It should not be used in cats with hypertrophic cardiomyopathy or glaucoma, in which β2-receptor stimulation would be detrimental.
Albuterol (salbutamol) is similar to terbutaline and may be used systemically in dogs and horses. Oral syrup, oral tablets, and oral extended-release tablets are available, but albuterol is more commonly used as inhalation therapy.
Clenbuterol is used in the treatment of recurrent airway obstruction in horses; it is not used in dogs and cats. It is available as an oral syrup and may be available as an injectable solution for IV injection in some countries. Results of efficacy studies for bronchoconstriction have been conflicting, but clenbuterol appears to significantly increase mucociliary transport in horses with the disorder. The dosage is increased gradually until a satisfactory clinical response is seen. If there is no response at the highest recommended dose, the horse is considered to have irreversible bronchospasm. It should not be administered chronically to horses with recurrent airway obstruction without concurrent anti-inflammatory therapy. The most common adverse effects of clenbuterol are tachycardia and muscle tremors. Clenbuterol inhibits uterine contractions, so it should be used during late pregnancy only if this effect is desired for obstetric manipulations. Clenbuterol is also a repartitioning agent; it directs nutrients away from adipose tissue and toward muscle. The result is increased carcass weight, increased ratio of muscle to fat, and increased feed efficiency. Because there is a significant human health risk from clenbuterol residues, it is banned in food animals in most countries and should not be used in horses that will be sent to slaughter.
The methylxanthines, particularly theophylline, are bronchodilators (see Table: Methylxanthine Bronchodilators). Once the mainstay of human asthma therapy, theophylline has a high incidence of adverse effects, and its use has diminished with the development of metered-dose or disk inhalers for local drug delivery. The methylxanthines have a variety of pharmacologic effects on various organ systems, including bronchial smooth muscle relaxation, CNS stimulation, mild diuresis, and mild cardiac stimulation.
The respiratory effects of methylxanthines are the result of several cellular mechanisms. Antagonism of adenosine is currently thought to be the most important action. Adenosine induces bronchoconstriction in asthmatic animals and antagonizes adenylate cyclase. Adenylate cyclase is responsible for the synthesis of cAMP, which controls bronchial smooth muscle relaxation and inhibits the release of inflammatory mediators from mast cells. Methylxanthines also inhibit phosphodiesterase, which further increases intracellular cAMP. They also inhibit calcium mobilization in smooth muscle, inhibit prostaglandin production, augment the release of catecholamines from storage granules, and increase the availability of calcium to contractile proteins of the heart and diaphragm. In addition to promoting bronchial smooth muscle relaxation, methylxanthines decrease the release of inflammatory mediators from mast cells and increase mucociliary transport.
Theophylline is available in several formulations, including injectable, aqueous solutions, elixirs, tablets, and capsules. Theophylline base is poorly soluble in water and often results in GI irritation when administered PO. Aminophylline is a theophylline salt that is 78%–86% theophylline. It is more water soluble and results in less GI irritation. Other theophylline salts, such as oxtriphylline (a choline salt), are available, and their theophylline content must be considered when developing a drug dosage regimen.
Several sustained-release formulations of theophylline are suitable for use in dogs and cats and may be administered less frequently than the regular formulations. After oral administration, theophylline is rapidly and completely absorbed. Therapeutic plasma concentrations, extrapolated from people, are 5–20 mcg/mL. Animals are sensitive to high concentrations of theophylline, especially after rapid IV administration, and toxicity may be seen with concentrations <20 mcg/mL. Theophylline tablets may become trapped in bezoars (such as hairballs in cats), and continued absorption can result in toxicity. Cardiac arrhythmias, CNS excitement, tremors, convulsions, and GI irritation may be seen. Theophylline undergoes enterohepatic recirculation, so activated charcoal is recommended if clinical signs are present, no matter how long after the drug was administered. Theophylline metabolism is inhibited by erythromycin, cimetidine, propranolol, enrofloxacin, and marbofloxacin; concomitant therapy can result in theophylline toxicity. Theophylline metabolism is induced by rifampin and phenobarbital, which may necessitate increasing the dose of theophylline.
Theophylline is used to treat both cardiac and respiratory diseases in dogs and cats. Theophylline is also used in management of intrathoracic collapsing trachea and various forms of canine bronchitis, but it is less effective than glucocorticoids such as prednisone. Theophylline or aminophylline was used in horses in the management of recurrent airway obstruction, but efficacy was often poor and use of these drugs has been replaced by β-agonist bronchodilators delivered by metered-dose inhalers.
The anticholinergic (parasympatholytic) drugs are effective bronchodilators that reduce the sensitivity of irritant receptors and inhibit vagally mediated cholinergic smooth muscle tone in the respiratory tract. Cholinergic stimulation causes bronchoconstriction; asthmatic individuals appear to have excessive stimulation of cholinergic receptors.
Atropine is primarily used as a preanesthetic to prevent bradycardia and reduce airway secretions, and as emergency therapy of dyspneic animals with organophosphate intoxication. Atropine is also used for bronchodilation in horses; a low IV dose (0.014 mg/kg) is more effective and less toxic than IV theophylline. A test dose of 0.022 mg/kg may also be used to determine prognosis in horses with recurrent airway obstruction; if pulmonary function does not improve with a test dose of atropine, successful management with bronchodilators is unlikely. Atropine should be used with caution, because even low doses may cause tachycardia, ileus, neurologic derangement, and blurred vision in horses.
Glycopyrrolate is twice as potent as atropine in people and does not cross the blood-brain barrier. Its onset of action is slower than atropine, but its duration of effect is longer. Information about use in horses is sparse, but doses of 2–3 mg can be given IM, bid-tid.
N-butylscopolammonium bromide is an anticholinergic drug approved to relieve spasmodic colic in horses. Unlike atropine, N-butylscopolammonium bromide does not cross the blood-brain barrier. Adverse effects are minimal and include transient tachycardia, decreased borborygmi, and transient pupillary dilatation. In horses with recurrent airway obstruction challenged with moldy hay, N-butylscopolammonium bromide was a potent bronchodilator, with maximum relief occurring 10 min after IV administration. The bronchodilatory effect is short lived, dissipating within 1 hr of drug administration.
The glucocorticoids inhibit the release of inflammatory mediators from macrophages and eosinophils but do not inhibit the release of granules from mast cells. Glucocorticoids decrease synthesis of prostaglandins, leukotrienes, and platelet-activating factor, which play important roles in the pathophysiology of respiratory tract inflammation. Studies suggest glucocorticoids enhance the action of adrenergic agonists on α2-receptors in the bronchial smooth muscle. Because of immunosuppressive effects, glucocorticoids are generally avoided in infectious respiratory diseases.
For severe attacks of canine bronchitis, feline asthma, or recurrent airway obstruction, parenteral injection of glucocorticoids usually provides rapid relief. For chronic therapy in dogs, oral prednisone is usually the drug of choice. Prednisone is a prodrug; it is metabolized by the liver to the active drug prednisolone. Pharmacokinetic studies have shown poor oral bioavailability of prednisone in cats and horses. Therefore, it is preferable to administer prednisolone to these species. In dogs, a typical anti-inflammatory dosage is 0.5–1 mg/kg, with chronic therapy on an every-other-day basis. A similar dose of prednisolone can be used in cats; if prednisone is used, higher doses may be necessary. Cats are somewhat resistant to the effects of glucocorticoids, and dosages of prednisone of 1 mg/kg/day may be necessary for chronic therapy of feline asthma. Alternatively, 20 mg of methylprednisolone acetate can be administered IM to asthmatic cats every 3 wk. For emergency treatment of dyspneic cats, a shock dose of an IV glucocorticoid (prednisone sodium succinate, 5–10 mg/kg; or dexamethasone sodium phosphate, 1–2 mg/kg) should be used. It is common for clinical signs to resolve in cats with feline asthma or chronic bronchitis that are treated with oral glucocorticoids despite persistent lower airway inflammation, so therapy should be tapered very carefully. Although prednisolone can be administered to horses, the small tablet sizes available make it inconvenient, so equine formulations of oral dexamethasone (10 mg/450 kg) are recommended. The injectable formulation of dexamethasone can be given IV to horses with acute bronchoconstriction and dyspnea. Flumethasone or isoflupredone may also be used in horses. Isoflupredone is as effective as dexamethasone in the treatment of recurrent airway obstruction in horses, but as in cattle, it is associated with hypokalemia.
Because of the role of serotonin in allergen-induced bronchoconstriction in cats, the serotonin antagonist/antihistamine cyproheptadine (2 mg, PO, once to twice daily) may be used as an adjunct to glucocorticoids and bronchodilators to block bronchoconstriction in chronically asthmatic cats. In experimental models of feline asthma, cyproheptadine decreased airway hyperreactivity but did not significantly decrease eosinophilic airway inflammation. However, pharmacokinetic studies of cyproheptadine suggest that some cats may require doses as high as 8 mg to reach therapeutic concentrations. Because of its long elimination half-life (12 hr), cyproheptadine requires several days to reach steady-state concentrations, and 4–7 days may be needed to see clinical effects. Serotonin antagonism in the appetite center stimulates appetite, so weight gain may be a problem. Lethargy, depression, and increased appetite may occur within 24 hr of initiating therapy.
Antimicrobial therapy may or may not be necessary in treatment of airway inflammatory diseases. Antimicrobial therapy should be started for cats with tracheobronchial cultures suggestive of a true bacterial infection or those positive for Mycoplasma. Mycoplasma spp can be isolated from healthy dogs but are not found in healthy cats. Doxycycline, azithromycin, and fluoroquinolones treat Mycoplasma infections effectively. Secondary bacterial infection from Streptococcus zooepidemicus may exacerbate inflammatory airway disease in horses and can easily be treated with penicillin, ceftiofur, or a trimethoprim/sulfonamide.