Inhalant Devices

With the advent of metered doses inhalers in the 1960s, beta-adrenergics became a common therapy for treatment of human asthma. Short-acting β₂ agonists administered by aerosol (Figure 20-5) include albuterol and its R enantiomer levalbuterol, metaproteronol, pirbuterol, bitolterol, and terbutaline (see Figure 20-4). Longer-acting (in humans) beta-2 adrenergic drugs tend to be more lipophilic and thus remain in the presence of a receptor for a longer time. Examples include salmeterol and formoterol (see Figure 20-4).^40,41,55 The drugs differ in their effect and use. Short-acting products are associated with rapid symptomatic relief in human asthmatics when used at appropriate doses. However, use at high doses has been associated with an increase in mortality in humans, leading to their recommended use on an “only as needed” basis.^40,55 On the other hand, improvement in pulmonary function in humans was sustained with prolonged used of long-acting beta-adrenergics,⁵⁵ and thus such use was not associated with a decrease in symptomatic relief afforded by short-acting drugs. The duration of onset of long-acting beta-adrenergics may be 1 or more hours. Although minimally effective by themselves for control of inflammation, long-acting beta-adrenergics appear to enhance responsiveness to glucocorticoids. Rebound hyperresponsiveness does not appear to occur with rapid discontinuation of the long-acting drugs. The development of tolerance (desensitization) has been discussed and is probably more likely with long-acting drugs.⁴¹ Because beta-adrenergics do not provide as much antiinflammatory control, their efficacy may be reduced in the presence of inflammation and combination therapy with an antiinflammatory drug (e.g., inhaled or systemic glucocorticoids), or use of theophylline may be indicated.^40,55

Figure 20-5 An example of a device commercially available, intended as an adapter for inhalant metered dose devices marketed for human use.

Drugs that block β₂-receptors such as propranolol are contraindicated in animals with bronchial disease. Inhalant devices are discussed more in depth in the following section.

Pharmacologic Effects

Methylxanthines include caffeine, a potent respiratory stimulant, and theobromine, a recognized canine toxicant from chocolate and theophylline (Figure 20-6). Theophylline has been the cornerstone of long-term bronchodilatory therapy in animals, particularly dogs. Its mode of action has been attributed to nonspecific inhibition of phosphodiesterases (PDEs) and increased concentrations of cAMP and cGMP (see Figure 20-1).^41,56 This mechanism has been controversial, however, because theophylline does not inhibit PDE at therapeutic concentrations. However, this may reflect the existence of PDE as various isoenzymes (at least 11 members to this superfamily, each located in different sites within the cell, some of which are inaccessible to drugs).^22,23,41 Inhibition of PDE4 and PDE5 results in bronchodilation whereas inhibition of PDE4 contributes to its antiinflammatory effects.⁴¹ The nonselective action of theophylline results in bronchodilation and inhibition of inflammation. Theophylline also is a competitive antagonist at adenosine receptors. The inhibitory neurotransmitter adenosine, which induces bronchoconstriction and during hypoxia and inflammation. Another mechanism by which theophylline induces bronchodilation, however, may be through interference of calcium mobilization.^22,23

Figure 20-6 Caffeine, which is used as a respiratory stimulant in humans, is metabolized to other methylxanthines, theobromine, theophylline, and paraxanthine.

Compared to beta-2 agonists, theophylline is considered a weaker relaxant of airway smooth muscle.⁴⁰ As with β-agonists, theophylline is equally effective in large and small airways. Theophylline has other effects in the respiratory system that are important to its clinical efficacy.^22,23,56 In addition to its bronchodilatory effects, it inhibits mast cell degranulation and thus mediator release (see Figure 20-3)⁵⁷; increases mucociliary clearance; and prevents microvascular leakage.⁵⁸ Its antinflammatory effects appear to include modulation of cytokines, particularly of macrophage origin.⁵⁹ Finally, antiinflammatory effects of theophylline may also reflect nuclear activation of histone deacetylase.⁴¹ Decreased TNF-α and IFN-γ and increased IL-10 (antiinflammatory) have been reported. Pentoxifylline has similar antiinflammatory effects; its IV administration is addressed in Chapter 29. Increased mucociliary clearance has been reported in dogs.⁶⁰ In propofol-anesthetized cats (n = 6), no treatment effect could be detected in the mucociliary transport rate after oral administration of 25 mg/kg of a slow release (Slo-bid) product. The ability to detect a significant difference was not addressed. Further, the mucociliary the rate in untreated animals (22.2 ± 2.8 mm/min) was perceived to be maximal, leaving no room for theophylline-induced increase. The impact of propofol is not clear, and theophyllline concentrations were not measured to confirm adequate concentrations. Thus the lack of efficacy may not reflect theophylline as much as failed delivery or altered response.

In addition to its antiinflammatory effects, a major advantage of theophylline, compared with other bronchodilators, may be its increased strength of respiratory muscles and thus a decrease in the work associated with breathing.^56,62,63 This may be important to animals with chronic bronchopulmonary disease.

Disposition

Theophylline is one of the few drugs active in the respiratory tract whose disposition has been studied in animals. Because theophylline is not water soluble, it can be given only orally. Salt preparations of theophylline are available for either oral or parenteral administration. Dosing of the various salt preparations must be based on the amount of active theophylline (Table 20-2). Aminophylline, an ethylenediamine salt, is 80% theophylline, whereas oxtriphylline is 65% theophylline, and glycinate and salicylate salts are only 50% theophylline. Regular aminophylline is well absorbed (bioavailability of at least 90%) after oral administration in both dogs and cats.^64,65 In dogs peak plasma drug concentrations for the theophylline base (approximately 8 μg/mL after a dose of 9.4 mg/kg) occur 1.5 hours after oral administration.⁶⁴ The volume of distribution (L/kg) and clearance (mL/min/kg) in dogs are, respectively, 0.59 ± 0.045 and 0.78 ± 0.13. The extrapolated peak concentration after intravenous administration of 11 mg/kg aminophylline (8.6 mg/kg theophylline equivalent) was 22.94 ± 5.8 μg/mL.⁶⁶ In cats extrapolated concentrations after 10 mg/kg intravenous aminophylline approximated 10 μg/mL; volume of distribution (L/kg) and clearance (mL/min/kg) were 0.87 ± 0.07 and 0.87 ± 0.16, respectively.⁶⁷ Interestingly, peak concentrations after intravenous or oral (sustained-release) products are higher in cats when dosed in the evening compared with the morning.⁶⁸

Table 20-2 Doses of Drugs Used To Treat Disorders of the Respiratory Tract

More than 30 slow-release preparations exist for use in humans. Although several products have been studied in dogs and cats,^68,69 their disposition is markedly variable and cannot be predicted on the basis of product name or description. Interchangability of products cannot be assumed, and monitoring is strongly encouraged to establish potential efficacy. For dogs, the rate of oral absorption of slow-release products is apparently faster than in humans. The extent of absorption varies with the preparation. Bioavailability of slow-release preparations varies from 30% (anhydrous theophylline 24-hour capsules; Theo-24, Searle Laboratories) to 76% (anhydrous theophylline tablets; TheoDur).⁶⁹ The least variation among animals occurs for oxtriphylline enteric-coated capsules (Choledyl-SA Tablets; Parke-Davis) and a 12-hour capsular anhydrous theophylline (Slo-Bid Gyrocaps), which are approximately 60% bioavailable. The minimum effective concenteration recommended for humans (10 μg/mL) may not be reached by all slow-release products. Plasma drug concentrations during a 12-hour dosing interval varies, by almost 120% for the oxtriphylline product but only 48% for the anhydrous tablet (Theo-Dur), suggesting it may be the best product for use in dogs.⁶⁹ However, neither Theo-Dur nor Slo-Bid Gyrocaps are currently available for use in the United States. Although the mean residence time of the slow-release preparation was significantly longer by 1 to 2 hours than that of the regular preparation in dogs, the clinical significance of this difference is questionable.⁶⁹ More recently, Bach and coworkers⁶⁶ described the disposition of a generic (Inwood Laboratories) extended-release theophylline tablet (Theochron) or capsule (TheoCap) in dogs (15.5 mg/kg orally; n = 6). The oral bioavailability (%) of the tablet and capsules was 98 ± 15.4 and 83.6 ± 18.5%, respectively. The C_max (μg/mL) was 17.4 ± 4.9 and 12.2 ± 2.8 for the tablet and capsule, respectively, whereas the elimination half-life was 10.9 ± 3.6 and 12.7 ± 2.7. Drug concentrations remained within the recommended therapeutic range for 12 hours. The authors concluded that 10 mg/kg every 12 hours would result in theophylline concentrations in the therapeutic range.

Cats also have been studied. Although it is not distributed to all body tissues, theophylline is characterized by a relatively large volume of distribution in dogs (0.7 to 0.8 L/kg) and a smaller volume in cats (0.41 L/kg).^64,69,70 Unlike human beings, distribution of theophylline is not limited by binding to serum proteins in dogs; serum protein binding is less than 12%.^71,72 Elimination of theophylline is not dose dependent in dose ranges of 3 to 15 mg/kg. Dye and coworkers^68,70 studied two sustained-release theophylline products (TheoDur and Slo-Bid Gyrocaps, William H. Rorer, Inc) in the cat. Although both products were reasonably (>75%) bioavailable in the cat, neither product is currently available in the United States. A more recent study addressed the disposition of a generic (Inwood Laboratories) extended-release theophylline tablet (Theochron; 15 mg/kg) and capsule (TheoCap; 19 mg/kg) in cats (n = 6).⁶⁷ The C_max (μg/mL) of the tablet and capsule was 17.8 ± 3.4 and 15.8 ± 3.1, respectively. Although bioavailability of both products was 100% or greater, the elimination half-life for the tablet and capsule was 13.6 ± 3.9 hour and 18.3 ± 8.0, respectively, compared with 11.7 ± 1.8 hour for the intravenous preparation (aminophylline), suggesting that the drugs did not always act in an extended-release manner in cats. Nonetheless, drug concentrations remained within the recommended therapeutic range for 24 hours. These data suggested that once-daily administration in cats should be sufficient to maintain concentrations within the therapeutic range. (see Table 20-2). A longer dosing interval might be acceptable if evidence supports an antiinflammatory effect at even lower concentrations. Based on a chronopharmacokinetic study of these sustained-release products, dosing in the evening rather than in the morning appears to be associated with better bioavailability and less peak plasma theophylline concentration fluctuation.⁶⁸ A disadvantage of the use of the slow-release products for small animals is the limited dose sizes available. The product cannot be divided for more accurate dosing without altering the kinetics of slow release.

Theophylline is metabolized by demethylation in the liver. Theobromine may be an active metabolite in some species. Different rates of metabolism result in variable clearance rates and drug elimination half-lives among animals, and doses consequently vary.⁷² For example, the elimination rate constant of theophylline is less in cats (0.089/hr)⁷³ than dogs (0.12/hr), resulting in a longer half-life in the cat (7.8 hours) compared with the dog (5.7 hours),^64,65 thus necessitating a smaller dose in cats.⁶⁹ Theophylline concentrations can be affected—most commonly increased—by a number of drugs, including fluorinated quinolones,⁷⁴ erythromycin and its congeners,⁷⁵ and cimetidine.⁷⁶

Adverse Reactions and Drug Interactions

Theophylline is associated with a wide range of adverse effects, including central nervous system excitation (manifested as restlessness, tremors, and seizures),⁷² gastrointestinal upset (nausea and vomiting), diuresis, and cardiac stimulation (e.g., tachycardia). In a retrospective study of theophylline toxicity in human patients, clinical signs included severe vomiting (89%), seizures (21%), and cardiac arrythmias (16%).⁷⁷ Vomiting precluded treatment with oral charcoal but responded to metoclopramide. Therapy included mechanical ventilation, anticonvulsants or sedatives, and muscle relaxants. Because of the risk of toxicity, intravenous use should be limited to patients who have not responded to β-agonist therapy and are facing life-threatening disease. Compared with the salt preparations, theophylline is more irritating to the gastrointestinal tract than aminophylline.^30,56 Rapid infusions or infusions of undiluted aminophylline can cause cardiac arrhythmias, hypotension, nausea, tremors, and acute respiratory failure.³⁰

Theophylline may be involved in a number of drug interactions; hepatic metabolism and potentially serious adverse effects should lead to cautious use with other drugs. Inhibition of drug-metabolizing enzymes by fluorinated quinolones has been described in human medicine and for both enrofloxacin and marbofloxacin in animals.⁷⁸ For enrofloxacin 5 mg/kg decreased theophyllline clearance by 43%⁷⁹; a different study found a 26% decrease by marbofloxacin (5 mg/kg).⁷⁸ This translates to an increase in C_max by 31% for theophylline, sufficient to contribute to toxicity. Indeed, the author has measured peak theophylline concentrations above 70 μg/mL and an elimination half-life of 19 hours in a dog concomitantly given enrofloxacin at 5 mg/kg. Clinical signs of theophylline toxicity emerged within 24 hours of beginning enrofloxacin therapy. Theophylline–terbutaline interactions do not appear to be clinically relevant, as has been shown in humans,⁸⁰ supporting their combined use for patients not responding to a single bronchodilator.

The application of therapeutic drug monitoring to guide therapy would assist in identifying the most appropriate dosing regimen, particularly when using slow-release preparations whose bioavailability might vary among patients, in patients receiving drug combinations that increase the risk of drug interactions, and in patients with hepatic dysfunction. Although a therapeutic range has not been established for small animals, the range recommended for humans (10 to 20 μg/mL) can be extrapolated until a more definitive range has been established. Dogs are apparently more tolerant of theophylline toxicity than are humans. In one study toxicity manifested as tachycardia, central nervous system stimulation (restlessness and excitement), and vomiting did not occur until plasma theophylline concentrations reached 37 to 60 μg/mL. Doses of 80 to 160 mg/kg of a sustained-release preparation were required to induce toxicity.⁸¹ In cats concentrations as high as 40 μg/mL do not induce adverse reactions, although salivation and vomiting are common after administration of more than 50 mg/kg, and seizures may occur at doses greater than 60 mg/kg.⁸²

The side effects of theophylline are dose dependent and might be prevented to a large degree by appropriate dosing. Therapeutic drug monitoring should facilitate the design of proper dosing regimens to prevent toxicity.

Pharmacologic Effects

Anticholinergic drugs compete with acetylcholine at muscarinic receptor sites.⁸³ In the respiratory tract, they reduce the sensitivity of irritant receptors and antagonize vagally mediated bronchoconstriction. The site of action of these drugs in the respiratory tract is controversial. In some studies bronchodilation is reported throughout the airways in asthmatic human patients and cats, whereas other investigators believe that the effects are confined to large airways.⁸³ The route by which anticholinergic drugs are administered influences their bronchodilatory effects. Despite their effect on bronchial airways, the anticholinergic drugs have not proved clinically effective in the treatment of bronchial diseases in animals, and their use is limited to treatment of bronchoconstriction associated with organophosphate toxicity or in animals in status asthmaticus unresponsive to bronchodilator therapy. The lack of clinical efficacy of anticholinergics may reflect nonselective drug–receptor interaction.^22,23 Thus far, three types of muscarinic receptors have been identified in airways. M₃ receptors release acetylcholine, whereas M₂ receptors block its release. Nonselective blockade of muscarinic receptors by atropine and ipratropium may actually potentiate acetylcholine release by antagonizing the effects of M₂-receptor stimulation. Drugs specific for M₃ receptors may ultimately lead to successful treatment of bronchial disease with anticholinergics drugs.^22,23 As with beta-adrenergic drugs, use of inhaled anticholinergic drugs reduces systemic adverse effects.

Atropine

Aerosolized atropine, a prototype anticholinergic drug, affects predominantly the central airways, whereas both central and peripheral airways are affected if the drug is administered intravenously.^22,23 Because atropine is highly specific for all muscarinic receptors, it causes a number of systemic side effects, including tachycardia, meiosis, and altered gastrointestinal and urinary tract function.⁶⁴ In the respiratory tract, atropine reduces ciliary beat frequency, mucous secretion, and electrolyte and water flux into the trachea. The net effect is decreased mucociliary clearance, which is undesirable in patients with chronic lung disease.⁶⁴ Aerosolization of atropine does not reduce the incidence of respiratory adverse reactions. Atropine is well absorbed (in humans) after oral administration. In humans atropine has proved most useful for treatment of chronic bronchitis and emphysema, diseases that are characterized by increased intrinsic vagal tone.⁸³ Its adverse effects on respiratory secretions and ciliary activity, however, apparently negate its benefits to bronchial tone during long-term administration in animals. The primary indication for atropine in small animals is facilitation of bronchodilation in acutely dyspneic animals. It is the treatment of choice for life-threatening respiratory distress induced by anticholinesterases. A combination of atropine with either β-adrenergic agonists or glucocorticoids will cause better bronchodilation than either drug alone.⁸³

Ipratropium Bromide

Ipratropium bromide is a synthetic anticholinergic that is pharmacodynamically superior to atropine. Although the two drugs are equipotent, ipratropium does not cross the blood–brain barrier. It is not well absorbed after aerosolization, which limits the likelihood of adverse effects. Ipratropium has been studied in the dog but not in the cat.⁸³ Of the anticholinergic drugs studied in dogs, ipratropium appears to cause the greatest bronchodilation (twice as much as atropine) with the least change in salivation.⁸³ When inhaled, it is more effective in preventing bronchoscopy-induced bronchoconstriction compared with intramuscular atropine.⁵⁴ Unlike atropine, it does not alter mucociliary transport rates.

Ipratropium bromide is generally not promoted as a bronchodilator in dogs or cats. However, with the advent of inhalant devices, this may change. The combination of salbutamol (120 mg, 1 puff) and ipratropium bromide (20 mg, 2 puffs) was found to be superior to either drug alone in the prevention of BAL-induced bronchoconstriction in experimentally induced allergen sensitive, conscious cats (n = 18).⁵⁴ Drugs were administered using a pressurized inhalant metered devices (pMDI). with a spacing chamber connected through an inspiratory valve to a face mask.

Glycopyrrolate

Glycopyrrolate can also be used as a bronchodilator in small animals. Although its onset of action is slower than that of atropine,³⁰ its half-life is 4 to 6 hours compared with 1 to 2 hours for atropine. The potency after systemic therapy has apparently not been compared between the two drugs, although glycopyrrolate is twice as potent when aerosolized. The systemic side effects of glycopyrrolate are minimal.

Cromolyn

Although the mechanism of action of cromolyn is not certain, it appears to inhibit calcium influx into mast cells, thus preventing mast cell degranulation and the release of histamine and other inflammatory mediators (see Figure 20-3).^22,23,84 At high concentrations, cromogylate inhibits IgE-triggered mediator release from mast cells.⁸⁵ Some studies suggest that the activation of inflammatory cells other than the mast cells (e.g., macrophages, neutrophils, eosinophils) is also inhibited by cromogylate.²⁸ Cromolyn is most useful as a preventive before activation of inflammatory cells. It is not significantly absorbed after oral administration and is characterized by a short half-life (=). Thus effective therapy depends on frequent aerosolization, which limits its utility in the treatment of small animal diseases. Currently, cromolyn is the safest drug used to manage asthma in humans.⁸⁴ It is associated with only minor side effects, and its discovery has revolutionized the management of bronchial asthma in people. Because of its wide therapeutic window and its apparent efficacy in the control of many inflammatory cells, its use in the control of small animal bronchial disease warrants further investigation.

Calcium Antagonists

The efficacy of calcium antagonists in the management of asthma has yet to be identified.⁸⁶ Their potential benefits include prevention of mediator release, smooth muscle contraction, vagus nerve conduction, and infiltration of inflammatory cells.^86,87 Most studies indicate that calcium antagonists have only a modest effect on airway smooth muscle contraction. Their antiinflammatory effects may ultimately prove of greater benefit.

Glucocorticoids

Glucocorticoid use in dogs and cats is addressed in Chapter 30. In 1997 the National Heart, Lung, and Blood Institute Expert Panel Guidelines recommended control of mild persistent asthma with a single, long-term control medication with antiinflammatory properties.⁵⁵ Accordingly, gluccocorticoids are the cornerstone of asthma therapy.⁸⁸ The antiinflammatory effects of glucocorticoids reflect an inhibitory effect on essentially all phases of inflammation. Airway infiltration with eosinophils, mast cells, and basophils is decreased, although the effect on T cell population in the lungs is less clear. Glucocorticoids differentially downregulate T_h2 cytokines, including IL-4, IL-5, and IL-13, but appear to upregulate T_h1 cytokines, including IFN-γ and IL-12. Most recently, glucocorticoids have been demonstrated to reduce eotaxin and other eosinophil-associated chemokines but have little effect on IL-8.⁸⁹ Glucocorticoids have little effect on cys-LTs.⁹⁰ Glucocorticoids have a “permissive” effect on β-adrenergic receptors and help prevent desensitization, which may accompany therapy with long-acting drugs.

Glucocorticoid efficacy for treatment of respiratory inflammatory disease depends on therapeutic concentrations in and below the epithelium of all diseased airways. However, whereas systemic therapy might provide the most consistent exposure to diseased airways, it also provides the greatest exposure to tissues other than the lungs, leading to adverse effects. A number of approaches have been taken to minimize adverse effects of systemic glucocorticoids when used to treat asthma. Although dogs and cats appear to tolerate glucocorticoids better than humans, making these approaches less important, they nonetheless may be beneficial to animals. These include selective gene targeting, increased potency for the glucocorticoid receptors (allowing administration in specialized [inhalant] drug delivery systems), and development of drugs that undergo first-pass metabolism. Aerosol administration minimizes many side effects. The preferred route in humans with mild disease is low-dose inhaled glucocorticoids.⁵⁵ Beclomethasone was among the first aerosol glucocorticoids developed for inhalant therapy.⁴⁰ Corticoisteroids marketed as inhalant metered devices (MDIs; see later discussion) in the United States include beclomethasone dipropionate (Beclovent), triamcinolone acetonide (Azmacort), flunisolide (Aerobid), budesonide (Pulmicort), fluticasone propionate (Flovent), and mometasone (Asmanex) (Figure 20-7).

Figure 20-7 Structures of selected “soft” glucocorticoids used in inhalant devices for the topical treatment of respiratory inflammatory diseases. These drugs are very potent and often are characterized by first-pass metabolism such that swallowed drug will be minimally absorbed.

Aerosolized glucocorticoids, such as occurs with MDIs, result in local delivery of higher concentrations. Although side effects are minimized, up to 90% of an inhaled dose is still deposited on the oral mucosa or pharynx and swallowed in humans; a similar or greater proportion might be anticipated in animals. Thus multiple methods have emerged to reduce adversities without decreasing efficacy. The delivery device may influence adverse effects. Systemic side effects associated with deposition of glucocorticoids on the pharynx and central airways and local side effects in the upper airway (e.g., dysphonia in up to 50% of the patients) led to the inclusion of “spacers” that removed larger particles before they penetrated the pharynx.⁴⁰

Corticosteroid delivery of MDIs also has been improved by the advent of hydrocarbon fluoroalkyl (HFA)–propelled MDI. Beclomethasone dipropionate delivery to peripheral airways increases from 5% to 15% for the chlorofluorocarbon -propelled preparation to 50% to 60% with the HFA propellant.⁹¹ Not only is total lung delivery increased, but the depth of penetration also is enhanced, a potentially critical improvement for controlling progression of the disease.

The glucocorticoid itself has been manipulated to decrease adversity. Corticosteroids marketed in MDI vary up to fivefold or more in potency. The relative potency of drugs marketed as MDI roughly follows the following order: monmetasone, which exceeds both fluticasone and budesonide, which, in turn, are 2 to 3 times more potent than beclomethasone; triamcinolone is the least potent of these drugs. While potency does allow administration of a small dose, it does not predict clinical efficacy of inhaled glucocorticoids.⁹¹ Despite sixfold differences in potencies among inhaled glucocorticoids, comparative clinical trials in humans have failed to demonstrate differences in efficacy when drugs are administered at equipotent dosages.⁹¹ Further, dose response curves for inhaled glucocorticoids tend to be flat, indicating that increasing doses is not likely to enhance efficacy.

Ultimately, differences in pharmaceutical (delivery) and pharmacokinetic properties largely determine variable responses to inhaled glucocorticoids. Inhaled corticosteroids generally are delivered as microcrystals, which must dissolve in the epithelial mucosal fluid. Crystals must be water soluble to ensure local delivery before the mucociliary tract removes the drug. However, alteration of dissolution times may also affect local delivery and thus local effects. For example, the dissolution time for budesonide is 6 minutes compared with beclomethasone dipropionate (5 hours) and fluticasone (8 hours). Lipophilicity of the drug enhances uptake and the duration of local effects. The addition of a halogen increases tissue retention compared with nonhalogenated drugs. Lipophilicity is greatest for beclomethasone and fluticasone followed by budesonide, with triamcinolone followed by dexamethasone and, finally, prednisolone as the least liphophilic. Not surprisingly, the most lipophilic of the drugs also is associated with the greatest number of side effects, including suppression of the hypothalamic pituitary adrenal axis. In humans, fluticasone is both the most potent and most lipophilic glucocorticoid. As such, it is characterized by the greatest evidence of systemic side effects. As such, recommendations for humans are that high-dose fluticasone propionate (>500 mg twice daily) be used only on the order of a physician and that the dose be titrated down to the lowest effective dose. Budesonide offers an example of a different type of manipulation that may allow longer dosing intervals while minimizing side effects. Because of its structure (a free C21 hydroxyl group) (see Chapter 30), excess intracellular budesonide complexes with long chain fatty acids. The complex is inactive but probably allows persistence of the drug at the site, much as a depot form would, with reversible esterification occuring as receptors are depleted of active drugs. Other drugs with a free C21 hydroxyl include triamcinolone, flunisolide, and ciclesonide, although long-chain fatty acid esterification has not been determined for them. Neither fluticasone, nor beclomethasone dipropionate, and probably mometasone, form fatty acid esters.⁹¹

Finally, although most devices require or allow twice- to four-times-daily dosing, those designed for once-daily administration also should enhance efficacy through improved compliance. Poor compliance with use of inhaled glucocorticoids in human patients also led to the development of combinations of steroids with long-acting β₂ agonists (e.g., salmeterol/fluticasone or formoterol/budesonide). Although compliance has improved, concern has arisen that the β₂ agonists will mask clinical signs that might otherwise indicate worsening of the disease.⁴⁰ Indeed, recent studies of the efficacy of inhaled beclomethasone diproprionate found improvements in clinical signs to be short-lived, probably because the inhaled drug does not control inflammation well.⁴⁰ Reduced airway caliber will further decrease efficacy by reducing drug delivery to the peripheral airways. Antiinflammatory therapy should target both large and small airways if inflammation is to be suppressed.⁴⁰ Thus systemic therapy should be considered (either as sole therapy or in addition to systemic therapy) in animals with moderate to severe disease. The peak effect of inhaled glucocorticoids may not occur for 1 to 2 weeks after therapy has begun.

Inhaled glucocorticoids have been recommended for use in cats with asthma,³⁹ although few studies have provided guidance. One abstract has reported a beneficial effect of flunisolide (250 μg/puff) but not zafirlukast (10 mg orally every 12 hours) in cats with experimental feline asthma.⁹² Reinero and coworkers⁹³ compared the impact of inhaled flunisolide (250 μg puff twice daily) to that of oral prednisone (10 mg/day orally) and placebo on indices of inflammation and adrenal gland suppression in healthy cats (n = 6). No treatment effect was apparent with regard to serum immunoglobulin or cytokine activity. The inhaled glucocorticoid was associated with lower baseline cortisol compared with placebo and and lower cortisol after adrenocorticotropic hormone stimulation compared with oral and placebo therapy. A limitation of the study may have been the use of prednisone rather than prednisolone as is suggested by impact on cortisol concentrations, although oral therapy did impact both T and B cells. This study supports the potentially inappropriate use of prednisone in cats and suggests that topical flunisolide therapy may suppress the hypothalamic pituitary adrenal axis in cats with flunisolide.

Drugs that Target Leukotrienes

LTs are very potent causes of marked edema, inflammation, and bronchoconstriction.⁹⁴ Their role in the pathophysiology of inflammation and their inhibition are discussed in Chapter 30. Their inhibition by glucocorticoids may be limited, leaving a void in therapy.⁹⁰ The approval of drugs that specifically inhibit the formation of LTs or their actions have offered a new avenue of control of respiratory inflammatory disease (e.g., asthma) in human medicine. Two classes of drugs have focused on their impact on LTs: LT synthesis (5-lipoxygenase) inhibitors (zileuton) and LT-receptor antagonists (LRAs). The latter class has proved to be more effective (Figure 20-8). Currently, two LRAs are approved in the United States: zafirlukast, administered twice daily, and montelukast, administered once daily. The disposition of neither drug has been studied in dogs or cats; in humans the dosing intervals reflect a half-life of 5 and 10 hours, respectively.

Figure 20-8 The arachidonic cascade and the formation of proinflammatory or antiinflalmmatory mediators catalyzed by lipoxygenases.

In human clinical trials, LRAs inhibit early- and late-phase bronchoconstriction and increased bronchial hyperresponsiveness in response to allergens; accumulation of inflammatory cells and mediators in bronchial lavage fluid; and acute bronchospasms stimulated by exercise, cold air, and aspirin.⁹⁵ Their bronchodilatory effects are less than that of long-acting β-adrenergics, whereas the antiinflammatory effects are less than those of glucocorticoids.⁹⁰ However, response does occur to single doses. In contrast to β-adrenergics, tolerance does not develop toward LRA effects. Their use has been associated with improvement of asthma either as sole therapy (instead of low-dose inhaled glucocorticoids) in mild to moderate asthma or as add-on therapy regardless of disease severity in glucocorticoid nonresponders.⁹⁵ The LRAs are well tolerated, particularly compared with glucocorticoids. A subset of asthmatics treated with LRAs have developed Churg–Strauss syndrome, a state of systemic hypereosinophilia. However, its emergence may reflect decreased doses of glucocorticoids permitted once LRAs are begun rather than a toxic effect of LRAs.⁹⁰

Recommendations regarding the role of LRAs in treatment of human asthma are dynamic. Currently, because they are less effective than glucocorticoids, their role as monotherapy is not recommended, even with mild disease. In contrast, LRAs have proved effective as monotherapy for treatment of allergic rhinitis in humans.⁹⁰ For asthma, because of their unique mechanism of action, LRAs have been combined with a number of other drugs used to treat asthma. For example, glucocorticoids minimally affect cys-LT; as such, combination with LRAs would be expected to have an additive effect, as has been demonstrated when combined with inhaled glucocortiocids. The combination of LRAs and glucocorticoids generally is as effective as glucocorticoids combined with β-adrenergic agonists. The use of an LRA as part of triple therapy (i.e., with corticosteroids, β-adrenergics) is a reasonable, albeit understudied, therapeutic approach in patients not responding to dual therapy. Finally, LRAs also have been recommended in the treatment of aspirin-sensitive asthma (discussed later).

The role of LTs in the treatment of feline asthma was previously discussed. Therapy with LRAs has had little scientific support, although this should not preclude their use, particularly in animals that have not sufficiently responded to or cannot tolerate (e.g., diabetics) corticosteroids. Receptors for LTs have yet to be identified in the smooth muscle of airways in cats; further, LTs have not been identified in the urine or plasma of cats with experimentally induced asthma.⁹² However, LTs were associated with experimentally induced heartworm disease in cats.⁹⁶ The recent approach to asthma as a systemic response mediated at the level of the bone marrow warrants consideration of the use of LRAs for treatment of feline asthma, particularly in nonresponders or patients that cannot tolerate glucocorticoids. Other potential indications would include control of inflammation in dogs in which glucocorticoids are contraindicated or pulmonary diseases characterized by eosinophilic infiltrate. Anecdotally, LRAs appear to be safe in both dogs and cats, although no study has confirmed their safety.

Nonsteroidal Antiinflammatory Drugs

The role of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of respiratory inflammatory diseases requires definition.^97,98 Both LTs and PGs are important in the pathophysiology of inflammatory diseases. Although NSAIDs effectively block PGs through inhibition of cyclooxygenase, they do not negatively affect lipoxygenase. Rather, in the aspirin-sensitive asthmatic (human) patient, aspirin and NSAIDs that selectively inhibit cyclooxygenase I shunt AA toward 5-lipoxygenas and the overproduction of cys-LTs.⁹⁰ They have no effect on other chemical mediators of inflammation. Additionally, NSAIDs nonselectively block all PGs, including those that provide some protection during periods of bronchoconstriction.⁹⁹ Some studies have shown that LT production increases in response to NSAID therapy, perhaps by providing more AA for lipoxygenase metabolism. Currently, labels include a contraindication for use in human patients with aspirin-induced asthma. However, although more studies are needed, thus far the newer NSAIDS generally are not associated with emergence of asthma.¹⁰⁰

Currently, the use of NSAIDs for the treatment of respiratory diseases in small animals is limited to aspirin therapy as treatment for thromboembolism associated with heartworm disease.^101,102 Aspirin is the preferred NSAID because at low doses it irreversibly inhibits TXA₂, an important contributor to pulmonary arterial vasoconstriction that accompanies thromboembolism. Current efforts in NSAID research are oriented toward identifying drugs that successfully inhibit both arms of the AA metabolic cascade or specific PG or LT inhibitors. The use of selective TXA₂ inhibitors for selected feline respiratory diseases is an example.⁴⁵ Among the NSAIDs that might be considered, are the dual inhibitors, such as tepoxalin, which target both PGs and LTs.

Antihistamines

A number of nonantihistaminergic drugs act to ameliorate the effect of histamine (Figure 20-9). However, in general, histamine is not recognized to be a major contributor to clinical signs of asmtha based on the limited control of clinical signs afforded by antihistaminergic drugs. Those drugs that prevent histamine release may be of most benefit because they will also prevent release of other inflammatory mediators associated with asthma.

Figure 20-9 Structures of selected antihistaminergic drugs, leukotriene receptor antagonsists, and miscellaneous drugs used to treat disorders of the respiratory tract.

Drugs that interact with beta receptors and stimulate cAMP depress histamine release. Thus epinephrine can be used prior to or early during anaphylaxis to reduce histamine release. However, most of the histamine has already been released by the time treatment occurs, and in fact, most of the beneficial effects of epinephrine during anaphylaxis result from physiologic antagonism of histamine-induced bronchoconstriction. Glucocorticoids impair histamine release through their permissive effects on beta-adrenergic receptors. Additionally, glucocorticoids are lytic to neoplastic mast cells. The newer (but not older) antihistamines such as cetirizine or loratadine may inhibit histamine release from mast cells.¹⁰³ These newer products have not been widely used in animals, although the disposition of several is discussed in Chapter 29.

The use of H₁ blockers may be detrimental in animals with chronic disease because of their effects on airway secretions.²⁹ The role of H₂ receptors in bronchodilation, mucous secretion, and inflammation suggests that H₂-receptor blockers should also be used with caution.^5,29 Among the drugs for which anecdotal discussion suggests efficacy for treatment of tracheal collapse is doxepin, a tricyclic antidepressant that is also characterized by marked H₁ antagonism. Efficacy may be related to antiinflammatory effects or some level of central nervous system depression.¹⁰⁴ Alternatively, local anesthetic actions may be contributing to efficacy.¹⁰⁵ Although not yet clinically available, drugs that specifically target H₄ receptors may prove useful through control of signals mediating chronic allergic responses. Cyproheptadine is an antiserotinergic, antihistaminergic drug. Because feline airways are exquisitely sensitive to the constrictor effects of serotonin, this drug may prove particularly useful in cats either alone or as an adjunct to bronchodilators or glucocorticoids.¹⁰⁶ The disposition of cyproheptadine has been described in cats (n = 6).¹⁰⁷ It is characterized by 100% oral bioavailability, a volume of distribution of 1 ± 0.5 l/kg and an elimination half-life of 12.8 ± 9.9 hours, supporting a once- to twice-daily dosing interval. A single intravenous dose of 2 mg was well tolerated. An oral dose of 8 mg yielded a C_max of 419 ± 99 ng/mL. Both the intravenous and oral dose were well tolerated. Studies following transdermal administration are pending.

Codeine

Codeine is the prototype narcotic antitussive and one of the most effective drugs available to suppress the cough reflex. Codeine phosphate and codeine sulfate can be used either alone or in combination with peripheral cough suppressants or decongestants. Over-the-counter preparations are available for human use. Compared with morphine, codeine is equally effective as a cough suppressant but is less suppressing to other central centers and causes less constipation. Side effects of codeine include nausea and constipation. Codeine is also addressed in Chapter 28.

Hydrocodone

Hydrocodone is a more potent antitussive than codeine but causes less respiratory depression. It is probably the most commonly used antitussive for dogs. Hydrocodone bitartrate is a hydrolysis product of dihydrothebaine.

Butorphanol

Butorphanol tartrate is probably more commonly used as an analgesic. Reclassified as a Schedule IV drug, it is now subject to the Narcotics Act. It is approved for use as an antitussive for dogs. As an antitussive, it is 100 times more potent than codeine and 4 times more potent than morphine.¹¹⁰ In dogs, after subcutaneous administration, butorphanol concentrations peak at 1 hour. Mean half-life is 1.7 hours, with a duration of activity of 4 hours or more. Butorphanol is characterized by a wide safety margin. The LD₅₀ in dogs after intramuscular administration is 20 mg/kg.¹¹¹ Therapeutic concentrations cause minimal cardiac or respiratory depression. Side effects include sedation, which can be significant and desirable; nausea; some diarrhea; and appetite suppression. The narcotic agonist/antagonist butorphanol tartrate is a potent antitussive when given orally or parenterally in dogs and cats.

Dextromethorphan

Dextromethorphan hydrobromide (see Figure 20-9) is a semisynthetic derivative of opium. It is the d-isomer of the codeine analog of methorphan. Unlike its L-enantiomer, levomethorphan, it lacks narcotic, direct analgesic, or addictive properties. It is an acid receptor antagonist and as such is also discussed in Chapter 28. Antagonists of NMDA receptors are powerful antitussives in some species (including humans). Dextromethorphan’s metabolite dextrorphan also is active. Because sedation is unusual after its use, it is classified as non-narcotic. Its antitussive mechanism is not certain; only the D-isomer has antitussive activity, which is similar to codeine in potency. Dextromethorphan interacts with sigma receptors (previously thought to be opioid receptors). Its onset of action is rapid, being fully effective within 30 minutes after oral administration. It is metabolized by CYP2D6, a drug-metabolizing enzyme found to be deficient in a significant proportion of the human population. Dextromethorphan is commonly found in over-the-counter cough preparations. It can be used safely in cats. In humans it can release histamine and therefore is not often recommended for atopic children. Its use with selective serotonin uptake inhibitors and monoamine oxidase inhibitors is discouraged. Studies in humans have shown that the combination of dextromethorphan with a bronchodilator is superior to dextromethorphan alone for the control of cough.¹¹²

Noscapine

Noscapine is a nonaddictive opium alkaloid (benzylisoquinoline) that has antitussive effects similar to those of codeine.¹¹³ Its use for small animals appears to be limited.

Therapy of Fungal Infections of the Nose

Nasal aspergillosis in dogs is difficult to treat and generally most successful if medical management is accompanied by surgical débridement. Topical therapy includes flushing the nasal mucosa with povidone–iodine solutions (10%) every 8 hours for 6 to 8 weeks after surgery; a 10% solution of clotrimazole in polyethylene glycol, instilled in nasal tubes and administered twice daily or in direct contact for 1 hour during surgical exploration; or enilconazole (10%) at 5 mg/kg instilled into nasal tubes twice daily for 7 to 14 days. Topical therapy should be accompanied by systemic therapy with itraconazole. Treatment of fungal infections is discussed in greater depth in Chapter 11.

Tracheitis

Resolution of underlying causes is important to successful control of the inflamed trachea. Noninfectious causes (e.g., exposure to smoke, cough) are more common than infectious causes. In addition to resolution of the underlying cause, drug therapy should be implemented to control symptoms. Cough can be controlled with peripheral or central antitussives or a combination thereof. Over-the-counter preparations that contain expectorants can prove helpful. Humidifying secretions (liquefaction of mucoid material) becomes increasingly important with chronic tracheitis and may include nebulization four to six times a day or exposure in a steam-filled bathroom for 15 to 20 minutes three times daily. Physical therapy (coupage) should be implemented after liquefaction of secretions. Short-term therapy with short-acting glucocorticoids may help break the cough cycle, although care must be taken that glucocorticoids do not exacerbate the underlying condition.

Antibiotics are indicated for infectious tracheitis/tracheobronchitis. Infectious tracheobronchitis in dogs (kennel cough) is a complex syndrome caused by multiple organisms, including viruses, bacteria, and mycoplasma. This syndrome is discussed with bronchial diseases.

Structural Disorders of the Trachea

Pharmacologic management of structural disorders of the trachea focuses on supportive therapy.

Bronchial Diseases

Diagnosis of bronchial diseases should be based on physical examination, thoracic radiography, tracheal or bronchial wash, and bronchoscopy. Examination for structural defects, cytologic studies, and microbial cultures are among the diagnostic tools of use for bronchial diseases.

Canine Infectious Tracheobronchitis

Bordetella bronchiseptica is the bacterial organism most commonly associated with kennel cough. Viral organisms include canine parainfluenza, canine herpes, and canine distemper viruses. The clinical syndrome is characterized by a dry, hacking, paroxysmal cough in an otherwise healthy animal. Clinical signs of this highly contagious syndrome generally appear 3 to 5 days after exposure. Tracheal cytology should reveal neutrophils and bacteria. Therapy of uncomplicated cases is supportive. Antitussives, in relative order of efficacy (least to most), include dextromethorphan (antitussives), butorphanol, and hydrocodone. Hydrocodone may be associated with sedation, which may be beneficial in cases of paroxysmal coughing. Antimicrobial therapy in uncomplicated cases (lasting 7 to 10 days) is discouraged; indeed, most antimicrobials used empirically (e.g., amoxicillin) generally do not penetrate bronchial secretions in sufficient quantities to be effective.

In contrast, antibiotic therapy (in addition to other supportive therapy) is indicated for complicated infections or for dogs whose coughing persists after 2 weeks and for which evidence exists of secondary bacterial infection. Other indicators of complications include any evidence of infection occurring lower than the upper bronchi or systemic signs of illness. Because of the complicated nature, and particularly if the patient has received previous antimicrobials, selection of the appropriate antibiotic should be based on a properly collected culture at the site of infection (not a pharyngeal or laryngeal swab). Selection of an antimicrobial empirically is complicated by the possibility of mycoplasma as a causative agent. Selection of antimicrobials for treatment of respiratory tract infections is discussed in Chapter 8.

Therapies intended to support mucociliary function should be continued. Because coughing associated with kennel cough can be paroxysmal, a single treatment with a short-acting glucocorticoid might be considered to ameliorate some of the effects of inflammation. In the immunocompromised animal, however, this may lead to spread of infection.

Feline Bronchial Diseases

Feline bronchial diseases include feline bronchial asthma as well as acute and chronic bronchitis and emphysema. It is characterized by damage or hypertrophy (or both) of the airway epithelium; increased production of airway secretions; and spasms of bronchial smooth muscle, which itself may become hypertrophied.³⁹ Causes of feline bronchial diseases have not been found, but a type I hypersensitivity reaction has been suspected as a cause of asthma. Initial contact between the allergen and bronchial mucosa may lead to the release of histamine and other mediators that allow penetration of the allergen into the submucosa. The resultant inflammatory response to the allergen leads to the characteristic disease. The source of inflammatory mediators includes essentially any cell of the respiratory tract, white blood cells, and platelets. Smooth muscle hypertrophy and increased mucus and inflammatory cell infiltrate (particularly eosinophils) characterize asthma and its clinical signs. Acute bronchitis is generally reversible and short in duration but can be life-threatening. Should airway inflammation persist, bronchitis may become chronic. Inflammation lasting 2 to 3 months can lead to deposition of fibrous tissue; these lesions tend to be irreversible. Emphysema can occur as a result of chronic bronchitis and is characterized by enlarged airspaces with destruction of bronchiolar and alveolar walls and airway collapse. Cough is the most consistent clinical sign of bronchial disease in cats. Respiratory distress may be absent or episodic, particularly in the presence of bronchial asthma.

Diagnosis should be based on thoracic radiographs, a complete blood count (which may reveal eosinophilia), tracheal or bronchial wash (particularly if bacterial or parasitic causes are suspected), and fecal examination (for parasitic causes). Cultures of Mycoplasma species should be performed whenever possible, particularly in nonresponders. Treatment should include environmental management. In particular, exposure to smoke (e.g., cigarette, fireplace) should be avoided; other potential environmental allergens include litter dust, perfumes, household cleaning products, deodorants, and insulation products. Asthma in cats has been classified according to the severity (mild, moderate, and severe) of clinical signs in order to facilitate the need for treatment.³⁹ However, clinicians are urged not to become too complacent in their approach to the disease and to ensure that seemingly mild disease does not progress to a more severe state in the absence of therapy. The primary focus of therapy is control of inflammation. Control of inflammation in peripheral airways may be paramount to successful therapy.

Management of Acute Asthma

Acute respiratory distress resulting from bronchial disease should be handled as a medical emergency. Administration of drugs should be accompanied by oxygen therapy and rest. The hydration status of the patient should be assessed at presentation and corrected if indicated. Overzealous fluid therapy can prove detrimental, however, and should be avoided. Therapy should include bronchodilators, glucocorticoids (for their permissive effect on β-₂ adrenergic receptors) and as necessary, anticholinergics.

Glucocorticoid therapy should be initiated in conjunction with bronchodilators in cats with status asthmaticus. The permissive effects of glucocorticoids are likely to improve response to bronchodilator therapy. Rapidly acting drugs such as prednisone sodium succinate should be administered at presentation and again at 4 to 6 hours.^6,30 Prednisolone is preferred to prednisone; the latter should not be given orally (see Chapter 30). Alternatively, dexamethasone or dexamethasone phosphate may be administered because of its antiinflammatory potency. Oral bronchodilator and glucocorticoid therapy can begin when the patient is stabilized.

Among the bronchodilators, β₂-adrenergic agonists are preferred (although doses have not been well established for animals), but nonselective agonists can be equally effective in critical cases. Parenteral rather than oral administration will ensure the most rapid onset of action, although use of a short-acting inhalant beta-adrenergic also might be considered (see the discussion of inhalant devices). Note that epinephrine has marked β₁ (and α) effects and in the presence of hypoxemia can cause fatal cardiac arrhythmias. Aerosolization should not replace, but can be used in concert with, parenteral administration if the stress of aerosolization is not dangerous to severely dyspneic animals. Subcutaneous epinephrine can be administered at presentation and, if the patient responds, repeated every 30 minutes for several doses.³⁰ Terbutaline can also be administered subcutaneously either instead of epinephrine or for animals that fail to respond to epinephrine. Aminophylline can be infused intravenously (2 to 5 mg/kg in 5% dextrose or saline) in animals that fail to respond to β-agonists.³⁰ The addition of atropine or glycopyrrolate may facilitate bronchodilation. Exacerbation of hypoxia is a complication of bronchodilator therapy, particularly with theophylline, due to drug-induced pulmonary vasodilation, and the potential for ventilation-perfusion mismatching necessitates administration of humidified oxygen. The use of an anticholinergic (atropine preferred) also should be considered after therapy with beta-adrenergics and glucocorticoids.

Reinero and coworkers¹⁴¹ addressed the impact of flunisolide (inhaled glucocorticoid), prednisone, zafirlukast, and cyproheptadine along with placebo on inflammatory mediators in an experimental model of feline asthma (n = 6) using a randomized crossover design. The only significant changes detected were a decrease in the percentage of eosinophils in bronchoalveolar lavage fluid for both prednisone and flunisolide compared with control and the content of allergen- (Bermuda grass) specific IGE in serum in cats receiving oral glucocorticoids. The power of the study to detect significant differences and the use of prednisone were limitations of the study.

Canine Chronic Bronchitis

Acute bronchitis is not as likely to present as a life-threatening situation in dogs and refers primarily to duration of clinical signs. Inflammation that persists more than 2 months may cause permanent damage to airways and is referred to as chronic bronchitis.¹⁴⁴ Bronchiectasis refers to irreversible dilation of the bronchi and can be a sequela of chronic bronchitis (inflammation) that does not resolve. The underlying cause is rarely identified but may include allergies; inhaled irritants (including cigarette smoke); viral, microbial, or parasitic infections; and heartworm disease. Bacterial infections are more difficult to diagnose, should be based on quantitative rather than qualitative assessment, and generally are not initiators of chronic disease.¹⁴⁴ Foreign bodies are a less common cause. As with cats, eradication of the underlying cause is paramount to halting the progression and therapeutic success. Diagnostic aids are the same as discussed for cats. Medical management of chronic airway disease in dogs is frustrating and should be approached as a perpetuating, slowly progressive, noncurable disease. As such, resolution of identifiable inciting causes (including triggers such as cigarette smoke) and conditions that confound success should accompany drug therapy. Owners may have to adjust their tolerance levels. Additionally, therapy should be accompanied by weight loss and physical therapy (mild exercise or coupage to facilitate movement of respiratory secretions).

Allergic bronchitis is not a common or easy diagnosis in dogs. The canine respiratory tract is probably more resistant to antigenic stimulation as a cause of cough compared with that of cats (and humans). Parasitic infections including heartworm disease must be ruled out. If airway cytology supports an allergic response and the underlying cause has not been identified or yet eradicated, glucocorticoids are indicated. A minimum effective dose should be rapidly established. Long-term glucocorticoid therapy may not be indicated for dogs unless the disease is associated with eosinophilic or mononuclear infiltrates; this is particularly true for patients with bronchiectasis.

Medical management of chronic bronchitis in dogs must be modified for the individual patient. Exposure to irritants such as secondary cigarette smoke must be avoided. Bronchodilator therapy provides the mainstay of medical management of chronic bronchitis in many dogs. Ideally, bronchodilators will also facilitate movement of secretions and control inflammation. Drugs used for cats can be used for dogs; the major difference is in frequency of administration, which will be more common in dogs. Response generally is based on improvement in clinical signs; therapeutic monitoring is encouraged for theophylline products, particularly for dogs that do not sufficiently respond and in dogs receiving delayed-release products intended for human use. Both terbutaline and albuterol can be used for dogs and might be considered in combination with theophylline for nonresponders for which therapeutic concentrations of theophylline have been maximized or on an alternating basis with theophylline.

Control of inflammation may be facilitated by the use of NAC; additionally, its expectorant and mucolytic effects also should prove beneficial. LRAs should be considered as well. Glucocorticoids should be used only if cytologic examination indicates a large mononuclear or predominantly eosinophilic component to the inflammation. Use should be implemented only after appropriate quantitative culture techniques have failed to yield microbes in the presence inflammatory cytology. However, the role of Mycoplasma also must be ruled out. Ideally, inhaled glucocorticoids are preferable to systemic. However, their role is less well established for dogs than for cats.

The routine use of antimicrobials for the treatment of chronic diseases is and potentially contraindicated. Distinction between infection and colonization should be made whenever possible. The risk of causing a resistant infection in the presence of a chronic progressive disease suggests that antimicrobial selection be based on quantitative culture (> 2.7 × 10³ colony-forming units/mL) based on a properly collected sample¹⁴⁴ and be designed such that microorganisms (and particularly first-step mutants) are killed (rather than inhibited). High doses for a shorter duration of time are preferred to doses that target the minimum inhibitory concentration of the infecting organism. Drugs that penetrate bronchial secretions well are preferred in the presence of adequate susceptibility. Selection of the antimicrobial should be based on culture and susceptibility data. Cytologic findings should be used to guide the need for antimicrobial therapy; culture data are likely to enhance therapeutic success. Antimicrobial therapy should target Bordetella. The potential of infection with Mycoplasma should not be overlooked. A trial course of antimicrobials is indicated if cytologic findings are supportive of microbial infection; care should be taken to use an antimicrobial effective against Mycoplasma before microbial infection is ruled out. In general, when possible, drugs that accumulate in phagocytic cells should be considered when treating pulmonary conditions. A more comprehensive discussion of antimicrobial therapy for respiratory tract infections can be found in Chapter 8.

The role of antitussives in the treatment of diseases depends on the character of the cough. Inflammation and infection can result in mediator release and cough without an increase in bronchial secretions. Narcotic antitussives are generally indicated if the cough is nonproductive and is paroxysmal and irritating in of itself. Use of glucocorticoids is indicated if airway inflammation is the major contributing factor (as opposed to accumulation of airway secretions). In the case of productive cough, the use of expectorants or mucolytic antitussives may exacerbate cough as is intended if accumulated debris is to be removed. Hydration of respiratory secretions is critical to effective mucociliary transport function. As such, diuretics are contraindicated, and daily water intake must be maintained. Exposure to humidified air (i.e., humidifiers, vaporizers, or a visit to the bathroom during family member showers) is likely to facilitate liquefaction of respiratory secretions.

Immune-Mediated Diseases

Diseases of the respiratory tract associated with eosinophilic infiltrates of the bronchi were discussed earlier with chronic causes of tracheobronchitis. Eosinophilic infiltrates that target lung parenchyma, referred to as pulmonary infiltrates with eosinophils, are associated with a spectrum of conditions ranging from mild diffuse infiltrates to granulomatous responses characterized by nodular masses that are visualized radiographically.

As with bronchial diseases, medical management of immune-mediated diseases should be accompanied by removal of any suspected allergen. Immunosuppressive doses of glucocorticoids are indicated for animals that do not respond to environmental changes. An exception is made for eosinophilic granulomatosis, for which cytotoxic drugs (cyclophosphamide) are indicated. For nongranulomatous disease, glucocorticoid therapy may need to be long term. Adherence to general principles of glucocorticoid use is indicated (i.e., tapering to a minimum effective dose, alternate-day therapy, and slow withdrawal). Granulomatosis, whether eosinophilic or lymphoid, is accompanied by a poor prognosis. Combination therapy should include cyclophosphamide (50 mg/m² orally every 48 hours) and immunosuppressive doses (1 mg/kg every 12 hours) of prednisone. NAC and bronchodilators should be used as previously discussed.

Pulmonary Hypertension

Because pulmonary hypertension is most commonly a secondary problem, treatment should focus on eradication of the underlying cause; its treatment is addressed in Chapter 14. Causes can be precapillary (alveolar hypoxia caused by lung disease or high altitude) or postcapillary (congenital heart disease with left to right shunting of blood or acquired heart disease). Dirofilariasis is probably the most common cause of pulmonary hypertension in dogs; bronchial asthma might be a cause in cats.

Pulmonary Edema

As in any tissue, excessive fluid accumulation in the lungs occurs as a result of increased hydrostatic pressure, decreased oncotic pressure, lymphatic blockage, or changes in vascular permeability. Increased hydrostatic pressure generally occurs as a result of volume (vascular) overload. In contrast to fluid dynamics in other tissues, hydrostatic pressure in the lungs is low, and lymphatic flow is high. Expansion of lymphatics, as well as fluid movement into the alveoli, can accommodate marked increases in capillary pressure. Thus capillary hydrostatic pressures must markedly increase for excessive fluid to accumulate in the lungs. Hypoalbuminemia is not a likely cause of pulmonary edema. Rather, vascular overload as a result of overcirculation is a common cause of pulmonary edema secondary to increased oncotic pressure. Left-sided heart failure is the most common cause of vascular overload. Regardless of the cause of pulmonary edema, oxygen therapy and actions that minimize stress and anxiety of the patient are indicated. Unless contraindicated, bronchodilators should be administered.

Diuretics are indicated for treatment of pulmonary edema associated with volume overload (increased hydrostatic pressure). Drugs that cause sodium and chloride excretion (i.e., furosemide) may be more effective, particularly in cases of sodium and water retention. Attention might be made to selection based on underlying cause (e.g., aldosterone antagonists in the presence of high aldosterone output). Diuretics are contraindicated for patients that are hypovolemic. Use in normovolemic animals should be cautious and the dose titrated to the minimum needed to control clinical signs associated with pulmonary edema. In life-threatening situations of pulmonary edema associated with volume overload, venous dilators can be used to increase the capacitance of the vascular system, thus “drawing” the increased volume into the veins, away from the heart and pulmonary system. Topically applied nitroglycerin or morphine sulfate (0.1 mg/kg intravenously as needed) can be used for this purpose. Morphine has the added advantage of sedating animals whose anxiety is contributing to hypoxia. Methylxanthines such as theophylline might be helpful in the short term because they also bronchodilate, and in the patient with heart failure they may improve contractility. They will also, however, increase oxygen demand by the heart, and their diuretic effects are short lived (2 to 3 days).

Pulmonary edema as a result of increased vascular permeability probably occurs more frequently than is anticipated. Any disorder that causes inflammation of the lungs will contribute to pulmonary edema of the lungs. The extreme manifestation of permeability-induced pulmonary edema is ARDS, which has been described in humans. The fluid contains protein that, as long as it is present, will continue to provide oncotic draw of fluid into the parenchyma. Pulmonary edema of this type is difficult to treat. Pulmonary wedge pressure is normal; vascular overload is not present. In this situation diuretics will serve to decrease fluid retention only at the cost of extracellular fluid volume and thus are not an effective treatment. Glucocorticoids might be indicated to decrease inflammation and support bronchodilation, although their use is controversial. Among the glucocorticoids, methylprednisolone should be considered because of its ability to scavenge oxygen radicals. Vasodilators might be used; the therapeutic intent of these drugs is not certain, but decreased delivery of blood to the lungs and a further decrease in wedge pressure may decrease movement of blood into the parenchyma. Vascular shunting and hypotension may, however, preclude their use. Newer therapies are likely to target mediators responsible for permeability, such as TNF or nitric oxide, or replace surfactant.

Aspiration Pneumonia

Clinical signs resulting from aspiration pneumonia may result from mechanical obstruction in small or large airways, and the inflammatory response to foreign materials (including gastric acid or other chemicals), bacterial infection is. Decreased pulmonary compliance and bronchoconstriction are likely to be a source of some of the clinical signs. Oxygen therapy, bronchodilatory therapy, and positive pressure ventilation are indicated, the latter particularly for patients with poor pulmonary compliance. Bronchoscopy can be used to guide removal of visible foreign material. Glucocorticoids might be used to minimize the inflammatory response during the initial phase of therapy; methylprednisolone and NAC might be considered to minimize oxygen radical damage. Immunosuppression probably negates the advantages of controlled inflammation after 48 hours of therapy. Among the drugs to be considered is pentoxifylline. Its early use (immediately after aspiration) as a loading dose followed by infusion resulted in 17% mortality versus 67% mortality in placebo-controlled rats.¹⁴⁵ In another study involving rats and measurement of inflammatory mediators, pre-treatment was found to be superior to post-aspiration treatment, suggesting preventative therapy might be considered in patients at high risk for post-operative aspiration. ¹⁴⁵ Routine antibiotic coverage should be avoided to minimize the risk of resistance until evidence of a bacterial component in the inflammatory process exists.

Near Drowning

Standard supportive therapy for near drowning includes oxygen, positive pressure ventilation, and therapy for shock. Bronchodilators may be of benefit. Using a rat model of hydrochloride-induced lung injury, pretreatment with pentoxifylline significantly reduced damage, with some benefit shown in animals whose treatment was withheld until post injury. Further, pentoxifylline administered as a continuous infusion significantly reduced lung injury in dogs in which near-drowning was experimentally induced.^145a Therapies for treatment of inflammation associated with aspiration should be considered. Use of glucocorticoids is controversial; however, use of methylprednisolone is appealing because of its oxygen-scavenging abilities. NAC therapy may be useful for its oxygen radical–scavenging effects as well as other benefits. Short-term therapy may be of benefit. Use of antimicrobials should probably be reserved for evidence of infection. Supportive therapy should also target the advent of cerebral edema; an additional advantage of using methylprednisolone is minimizing oxygen radical damage in the event of cerebral hypoxia.

Smoke Inhalation

Oxygen therapy is critical for removal of carbon monoxide; the half-life of carboxyhemoglobin decreases from 4 to 0.5 hours in the presence of 100% oxygen. Other supportive therapy includes airway hydration (as needed), bronchodilators, and (if indicated) positive pressure ventilation, and drugs intended to control inflammation.¹⁴⁷ Short-term administration of glucocorticoids (methylprednisolone preferred) may be of benefit to minimize inflammation and oxygen radical damage and to facilitate bronchodilation. However, pentoxifylline should also be considered. Using an ovine model, pentoxifylline administered continuously after induction of smoke inhalation injury was associated with less hypoxia and ventilation perfusion mismatching, pulmonary hypertension and markers of inflammation.¹⁴⁷