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β-Adrenergic Agonists
The β-adrenergic agonists have beneficial effects in the treatment of bronchoconstrictive respiratory tract diseases (see Systemic Pharmacotherapeutics of the Respiratory System: 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.
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Table 2
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β-Adrenergic Receptor Agonist Drugs |
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Drug
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Dosage
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Epinephrine
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Dogs: 0.05–0.5 mg, intratracheally or IV
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Cats: 0.1 mg, IV or IM
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Large animals: 0.1 mg/kg, IV, SC, or IM
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Isoproterenol
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Dogs: 0.1–0.2 mg, IM or SC, qid
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Cats: 4–6 μg, IM, every 30 min as needed
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Horses: 0.4 μg/kg, IV (diluted)
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Terbutaline
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Dogs, cats: 0.1 mg/kg, SC, every 4 hr, or 0.03 mg/kg, PO, tid
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Horses: 0.0033 mg/kg, IV, or 0.2–0.6 mg/kg, PO, bid
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Albuterol
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Dogs: 0.05 mg/kg, PO, tid
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Horses: 8 μg/kg, PO, bid
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Clenbuterol
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Horses: 0.8–3.2 μg/kg, PO, bid
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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). For cats with feline asthma that experience frequent, severe bronchoconstrictive episodes while on chronic glucocorticoid therapy, injectable terbutaline can be dispensed to clients with instructions to administer 0.01 mg/kg, SC, to abort episodes at home within ~15 min. 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. It may be used concurrently with methylxanthine bronchodilators.
Albuterol
(salbutamol) is similar to terbutaline and is used systemically in dogs and horses.
Clenbuterol is used in the treatment of recurrent airway obstruction in horses. 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. The most common adverse effects 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 and should not be used in horses that may be sent to slaughter.
Methylxanthines
The methylxanthines, particularly theophylline, are bronchodilators (see Systemic Pharmacotherapeutics of the Respiratory System: 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 local drug delivery by metered dose or disk inhalers. 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.
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Table 3
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Methylxanthine Bronchodilators |
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Drug
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Dosage
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Theophylline (parenteral)
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Dogs: 10 mg/kg, IV (slow) or IM
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Horses: 15 mg/kg, IV (slow)
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Theophylline (oral)
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Dogs: 5–7 mg/kg, PO, tid
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Cats: 3 mg/kg, PO, bid
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Horses: 10–15 mg/kg, PO, bid
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Theophylline (extended-release tablets)
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Dogs: 20 mg/kg, PO, sid
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Cats: 25 mg/kg, PO, sid
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Horses: 15 mg/kg, PO, sid
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Aminophylline (parenteral)
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Dogs: 10 mg/kg, IV (slow)
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Cats, horses: 5 mg/kg, IV (slow)
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Aminophylline (oral)
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Dogs: 10 mg/kg, PO, tid
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Cats: 5 mg/kg, PO, bid
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Horses: 15 mg/kg, PO, bid
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The respiratory effects of methylxanthines are due to 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 oxytriphylline (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 μg/mL. Animals are sensitive to high concentrations of theophylline, especially after rapid IV administration, and toxicity may be seen with concentrations <20 μg/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 for the treatment of both cardiac and respiratory diseases in dogs and cats. Theophylline is also used in the 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 their use has been replaced by β-agonist bronchodilators. There is little clinical experience with the use of theophylline in cattle; experimental evidence suggests that it is a poor bronchodilator in this species.
Anticholinergic Drugs
The anticholinergic (parasympatholytic) drugs are effective bronchodilators that act by reducing the sensitivity of irritant receptors and by inhibiting 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 acute bronchodilation in horses, in which a low IV dosage (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, as 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.
Glucocorticoids
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 diseases. 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, as it is hepatically metabolized to the active drug prednisolone. Pharmacokinetic studies have shown that cats and horses poorly metabolize prednisone to prednisolone. In dogs, a typical anti-inflammatory dosage is 0.5–1.0 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 1.0 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. While 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.
Cyproheptadine
Because of serotonin's role in allergen-induced bronchoconstriction in cats, the serotonin antagonist cyproheptadine (2 mg, PO, sid-bid) may be used as an adjunct to glucocorticoids and bronchodilators to block bronchoconstriction in chronically asthmatic cats. Because of its long elimination half-life (12 hr), it requires several days to reach steady-state concentrations and may take 4–7 days to be clinically effective. Cyproheptadine's 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
Antimicrobial therapy may or may not be necessary in the treatment of airway inflammatory diseases. Antimicrobial therapy should be started for cats with tracheo-bronchial cultures suggestive of a true bacterial infection or those positive for Mycoplasma. Mycoplasma spp can be isolated from normal dogs but are not found in normal cats. Doxycycline, azithromycin, and fluoroquinolones are effective for treating Mycoplasma infections. 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.
Last full review/revision March 2012 by Patricia M. Dowling, DVM,MSc, DACVIM, DACVCP
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