UPDATE ON RESPIRATORY DISEASES

0195-5616/92 $0.00

+ .20

RESPIRATORY THERAPEUTICS Dawn Merton Boothe, DVM, MS, PhD, and Brendan C. McKiernan, DVM

Treatment of small animal respiratory diseases tends primarily to target bronchodilators. Although this is not inappropriate, recent advances in the understanding of respiratory diseases have underscored the importance of inflammatory mediators in the pathophysiology of respiratory diseases. 6- 9• 17• 59•. 76 Drug therapy of the respiratory tract in small animals is most successful when it is based on a knowledge of its normal physiology and the pathophysiology of its diseases. NORMAL RESPIRATORY PHYSIOLOGY Airway Caliber Changes

Nervous innervation to the smooth muscle of the respiratory tract is complex. The parasympathetic system provides the primary efferent innervation, with acetylcholine as the primary neurotransmitter.54• 71 These fibers are responsible for the baseline tone of mild bronchoconstriction that characterizes the normal respiratory tract. The sympathetic system balances these effects by stimulating beta2-receptors to induce bronchodilation. In contrast, alpha-adrenergic stimulation can contribute to bronchoconstriction. 52 • 71 A third, not well understood nervous system, referred to as the nonadrenergic-noncholinergic (NANC) system or purinergic system, also innervates bronchial smooth muscle. 35• 54 This system mediates bronchodilation via vagal stimulation. The afferent fibers of this system are probably irritant receptors. Although the From the Department of Veterinary Physiology and Pharmacology, Texas A&M University College of Veterinary Medicine, College Station, Texas (DMB); and the Department of Veterinary Clinical Medicine, University of Illinois College of Veterinary Medicine, Urbana, Illinois (BCM)

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 22 • NUMBER 5 • SEPTEMBER 1992

1231

1232

BOOTHE & McKIERNAN

neurotransmitter has not yet been conclusively identified, vasoactive intestinal peptide has been implicated in the cat. 2• 3 Malfunction of this system has been associated with bronchial hyperreactivity, which often characterizes asthma. 35 The intracellular mechanisms that transmit signals from the nervous system to smooth muscle depend in part upon changes in the intracellular concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Fig. 1). The effects of these two secondary messengers are reciprocal, so that increased intracellular concentrations of one is associated with decreased concentrations of the other. Cyclic AMP is decreased by alpha-adrenergic stimulation and increased by beta2-receptor stimulation. In contrast, cyclic GMP is increased by stimulation of muscarinic (cholinergic) and, indirectly, histaminergic receptors (Fig. 1). The relative sensitivity of

{

isoproteranol epinephrine ephedrine terbutaline glucocorticoids

contraction

\.______ +

cGMP

(LTC,, LTD,) (PGD2 • PGF2 • TXA2 ) serotonin PAF

• I

/\ Ca' • _ ..,..- histamine

-

prevent release

-

- -

- THEOPHYLLINE

acetylcholine

•

I atropine

Figure 1. Factors determining bronchial smooth muscle tone. Reciprocal changes in cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) determine muscle tone. Contraction occurs when cAMP levels are decreased by events such as betaadrenergic stimulation or when cGMP levels increase in response to muscarinic receptor (M3) stimulation by acetylcholine or H1-receptor stimulation by histamine. Calcium (Ca2 •) and several mediators can also induce bronchoconstriction. Increased cAMP levels induced by beta-adrenergic or histamine (H2)-receptor stimulation will counteract muscle contraction. Inhibition of phosphodiesterases (PDEs) will also cause an increase in cAMP levels. Although the effects of most inflammatory mediators are best counteracted by preventing their release (see Fig. 3), several drugs may be used to antagonize smooth muscle contraction regardless of the etiology. LT = leukotriene; PG = prostaglandin; TXA = thromboxane; PAF = platelet-activating factor. Solid arrow = induces; broken arrow = inhibits. (From Boothe DM: Feline respiratory pharmacology. In Sheba Symposium Proceedings. Trenton, NJ, Veterinary Learning Systems, 1990, p 28; with permission.)

RESPIRATORY THERAPEUTICS

1233

bronchial smooth muscle to histamine- and acetylcholine-induced bronchoconstriction varies with the location and species. Peripheral airways in dogs are more susceptible to acetylcholine than in cats; cat airways, in general, are more sensitive to acetylcholine than histamine. 19 Smooth muscle receptors are also susceptible to stimulation by a variety of chemical mediators (Fig. 1), which also may modulate cAMP and cGMP. Control of bronchial smooth muscle tone is very complex and depends upon input from sensory receptors. At least five types of sensory receptors have been identified in cat lungs, all of which ~an be classified as irritant (or mechanoreceptor), stretch, and J-receptors. 35 All appear to be innervated by the parasympathetic system. Irritant receptors, located beneath the respiratory epithelium, occur in the upper airways. 71 In cats, they occur as far peripherally as the alveoli. 54 Physical, mechanical, or chemical stimulation of these receptors results in tachypnea, bronchoconstriction, or cough. Air flow velocity appears to be an important factor determining stimulation of irritant receptors in the upper airways. 54 Airway constriction sufficient to cause air flow velocity to exceed a specific threshold results in a vagally mediated cough reflex and bronchoconstriction. Airways also can be occluded by mucus and edema or narrowed by chemical mediators released during upper airway infections. 35

Respiratory Defense Mechanisms

In addition to the cough and sneeze reflexes, two other systems provide the major defense of the respiratory tract against invading organisms or foreign materials: the mucociliary apparatus and the respiratory mononuclear phagocyte system (MPS). 71 The mucociliary apparatus is the first major defense. It consists of the ciliary lining of the tracheobronchial tree and the fluid blanket surrounding the cilia. Two types of secretions form the fluid blanket of the respiratory tract. The cilia must be surrounded by a low-viscosity, watery medium to maintain their rhythmic beat. A more mucoid layer lies on top of the cilia. The synchronous motion of the cilia causes movement of the mucus layer and any trapped materials towards the pharynx. Changes in the viscoelastic properties of mucus that cause it to become either too watery or too rigid result in mucus transport that is less than optimal and interfere with the clearance of material from the respiratory tract.71 Mucus released by goblet cells results from direct irritation71 and is not amenable to pharmacologic manipulation. Surface goblet cells, which are uniquely prominent in feline bronchioles/ 8 increase in numbers with chronic disease. Submucosal glands of the bronchi secrete both a serous and mucoid fluid. The secretions tends to be more fluid than that of the goblet cells, but the degree varies with the stimulus. The normal consistency of the combined secretions of the tracheobronchial tree is 95% water, 2% glycoprotein, 1% carbohydrate, and less than 1% lipid. 71 Glycoproteins increase the viscosity of the secretions,

1234

BOOTHE & McKIERNAN

providing protection and lubrication. Parasympathetic, cholinergic stimulation increases mucus secretion, whereas beta-adrenergic stimulation causes secretion of mucus, electrolytes, and water. 12• 71 The second major component of the pulmonary defense system is the respiratory MPS. In cats, this includes both alveolar macrophages and the pulmonary intravascular macrophages (PIMs). 78 The PIMs represent a resident cell population in the feline respiratory tract. As with other cells of the MPS, they are characterized by phagocytic properties and thus cause the release of inflammatory mediators. The clearance of blood-borne bacteria and particulate matter in cats is accomplished by PIMs rather than hepatic Kupffer cells and splenic macrophages as in most other species.78 The pharmacologic significance of the MPS revolves around their role in inflammation (Fig. 2). The involvement of PIMs in both experimental and natural respiratory diseases of cats suggests that release of chemical mediators from these cells might be important in the pathogenesis of feline bronchial diseases. INFLAMMATORY MEDIATORS IN THE RESPIRATORY TRACT

Histamine is a vasoactive amine stored in basophils and mast cells. Airway mast cells are located primarily beneath the epithelial basement

cationic drugs immune complexes (lgE) complement (C3., cs.) others -..............

/PGS

J/

"LTs

•

histamine serotonin

ECF PGs, LTs, PAF

/

PAF M3

+

acetylcholine

Figure 2. The formation of mediators important in the pathogenesis of respiratory disease. Leukocytes and other cells release arachidonic acid (AA) metabolites and platelet-activating factor (PAF) following activation of phospholipases by a variety of stimuli. Mast cell degranulation induced by both immune and nonimmune stimuli is accompanied by AA metabolism as well as the release of preformed mediators, which are stored in the granules. Intracellular mechanisms that induce mast cell degranulation include increased calcium (Ca2 +), increased cyclic guanosine nucleotide (cGMP) mediated by muscarinic (M3) receptors, or decreased cyclic adenosine nucleotide (cAMP) mediated by beta-adrenergic receptor stimulation. PDE = phosphodiesterases; PGs = prostaglandins; LTs = leukotrienes; ECF = eosinophil chemotactic factor. (From Boothe DM: Feline respiratory pharmacology. In Sheba Symposium Proceedings. Trenton, NJ, Veterinary Learning Systems, 1990, p 31 ; with permission.)

RESPIRATORY THERAPEUTICS

1235

membrane in dogs. 29 Histamine produces a variety of effects (Table I) by interacting with specific receptors on target cells. At least three histamine receptors have been identified, 5 • 8• 16 two of which have been found in the trachea of the cat. 16• 52 Interaction with the HI-receptor causes an increase in intracellular calcium, and, ultimately, in cGMP (Fig. 2). 8 Histamine also stimulates cholinergic receptors in the airway. 8• 29 Histamine causes constriction in both central and peripheral airways in dogs and cats. 19• 29 The effects of histamine so closely. mimic the pathophysiology of early asthma that, for many years, histamine was considered the major cause of the syndrome. 8 However, lack of clinical response to HI-receptor antagonists led to the realization that other factors are more important. In contrast to HI-receptors, stimulation of H2-receptors causes an increase in cAMP and bronchodilation. 8 Thus, antihistamine drugs that block H2-receptors may be contraindicated in asthma. Recent studies have suggested that a defect in H2receptors may contribute to airway hyperreactivity.8 Histamine contributes to bronchial occlusion by mechanisms other than bronchoconstriction. Mucus secretion is mediated via H2-receptors and secretion of ions and waters via HI-receptors. 8 Microvascular leakage caused by contraction of endothelial cells also follows HIreceptor stimulation. 8 Histamine is chemotactic to inflammatory cells, particularly eosinophils and neutrophils. Interestingly, histamine stimulates T-lymphocyte suppressor cells via H2-receptors; 15 this function also may be depressed in human patients with asthma. 8 Histamine also has a negative feedback effect on further histamine release mediated by IgE. 8 These latter two effects are mediated by H2-receptors and are inhibited by H2-receptor antagonists. 15 · Serotonin (5-hydroxytryptamine, 5-HT) is released during mast cell degranulation. 8 Although serotonin does not appear to be an important mediator of human or canine bronchial asthma, both the central and peripheral airways in cats are very sensitive to its bronchoconstrictive effects following aerosolization or intravenous administration. 19 Constriction may reflect interaction with serotonin receptors or enhanced

Table 1. EFFECTS OF MEDIATORS OF INFLAMMATION Mediator

BC

Histamine Serotonin LTB4 LTC4 LTD4 PGD 2 PGE2 PGF2 PAF

+ + + + + + + + +

BD

VD

VP

CT

MS

+

+ +

+

+

+

+ + +

+

+ +

+ + + +

+

LT = leukotriene; PG = prostaglandin ; PAF = platelet-activating factor; BC = bronchoconstriction; BD = bronchodilation ; VD = vasodilation; VP = vascular permeability; CT = chemotaxis; MS = mucus secretion.

1236

BOOTHE & McKIERNAN

release of acetylcholine. Serotonin also may cause profound vasoconstriction of the pulmonary vasculature and microvascular leakage. 8 Prostaglandins (PGs) and leukotrienes (LTs) are eicosanoids that are formed when phospholipase A2 is activated in the cell membrane in response to a variety of stimuli (Fig. 2). Arachidonic acid (AA) is subsequently released from phospholipids and enters the cell. In the cell, it is converted by cyclooxygenases to inflammatory but unstable cyclic endoperoxides. The action of various synthetases and isomerases on the endoperoxides results in the final prostaglandin products, including PGE2 , PGF2., PGD2 , prostacyclin or (PGI2), and thromboxane (TXA2 ). The amount of each prostaglandin produced in the lung varies with the cell type and species. The effects of the various PGs tend to balance one another. PGD2 , PGF2., and TXA 2 cause bronchoconstriction, whereas PGE 1 and, to a lesser extent, PGI 1 cause bronchodilation. 8 ' 54 Bronchoconstriction induced by PGD2 is about 30 times as potent as that induced by histamine. Imbalances between PGs may be important in the pathogenesis of bronchial disease. Both PGD2 and TXA2 have been implicated in immediate bronchial airway hyperreactivity.8 TXA2 appears to be the predominant AA metabolite produced by cat lungs, 51 although other prostaglandin mediators also are important. 18 Lipooxygenases in the lung catalyze the conversion of AA to hydroperoxyeicosatetraenoic acid (HPETEs), which are further metabolized to several hydroxy acids (HETEs) and LTs {Fig. 2). All of these products are biologically active in the respiratory tract (Table 1), 8 and some are the most potent inflammagens known. Antigenic challenge results in the selective activation of 5-lipooxygenase, the enzyme that ultimately results in the formation of LTC4 and LTD. These LTs are the components of slow reactive substance, an important mediator released in the lungs during anaphylaxis. 8 Eosinophils also preferentially activate 5-lipooxygenase. 8 Bronchial smooth muscle contraction and microvascular permeability mediated by LTC4 and LTD4 is 100- to 1000-fold more potent than that induced by histamine. Both LTs are potent stimulators of mucus release in the dog but appear to be less potent in the cat.8 LTB4 , produced by macrophages, is the most potent chemotactant of the LTs. Platelet-Activating Factor (PAF) is formed following activation of phospholipase A2 in all membranes. It is a potent, dose-independent constrictor of human airways, and it is the most potent agent thus far discovered in causing airway microvascular leakage. 9, 17 PAF is also a potent chemotactant for platelets and eosinophils, both of which are a rich source of PAF. The effects of PAF may be mediated through LTs. 1 PAF has been implicated as the cause of sustained bronchial hyperresponsiveness, which characterizes asthmatics. 17 The role of PAF in feline and canine respiratory diseases has not been addressed. However, eosinophils are a major cell type associated with some feline and canine bronchial diseases, 53 and it is likely that PAF might be an important inflammatory mediator in these species.

RESPIRATORY THERAPEUTICS

1237

PATHOGENESIS OF ASTHMA

Although it is not the only chronic condition of the feline respiratory tract, eosinophilic bronchopulmonary disease (or feline bronchial asthma) provides a good model for discussing the pathophysiology of disease and targets of drug therapy. The interaction of sensory receptors and mediators of bronchial tone is intricately balanced in the normal lung. However, a series of pathologic disturbances severely di?rupts the balance in bronchial asthma. Asthma is a pathologic state of the lungs characterized by marked bronchoconstriction, inflammation, and airway hyperreactivity. 6 • 7• 29• 59· 75 Mediators released during inflammation are the major contributors to the pathogenesis of this disease. 6- 9 • 17• 59 • 80 Studies in several species have shown that stimulation of mast cells, macrophages, and other cells lining the airways cause changes in mucosal epithelial permeability.8 As permeability increases, histamine and other inflammatory mediators are better able to reach and stimulate inflammatory cells located in the submucosa . The release of more mediators is associated with stimulation of afferent nerve endings in the mucosa and reflex cholinergic bronchoconstriction. Mediators also increase microvascular permeability, induce chemotaxis, and stimulate mucus secretion. The release of cytotoxic proteins and toxic oxygen radicals further damages the respiratory epithelium, and the bronchial tree becomes hypersensitive. Mediators also can inhibit mucociliary function. 59 Airway obstruction in chronic disease reflects bronchoconstriction , bronchial wall edema, and accumulation of mucus and cells. As the disease progresses, airways eventually become plugged and ultimately collapse. Chronic inflammation leads to fibrosis, which contributes to the collapse, and air trapped within the alveoli can result in emphysema. DRUGS USED TO MODULATE THE RESPIRATORY TRACT

The syndrome of chronic bronchial disease is best treated by breaking the inflammatory cycle while immediately relieving bronchoconstriction. Thus, anti-inflammatory and bronchodilator drugs represent the cornerstone of therapy in many of the bronchial diseases encountered in d ogs and cats. Other categories of drugs that are effective for the management of respiratory diseases in small animals include antitussives, respiratory stimulants, and decongestants. Antimicrobials are indicated for control of infectious diseases. Bronchodilators and Anti-inflammatory Agents

Because of a shared mechanism of action, many drugs that induce bronchodilation also reduce inflammation. Bronchodilators reverse air-

1238

BOOTHE & McKIERNAN

way smooth muscle contraction by increasing cAMP, decreasing cGMP, or decreasing calcium ion concentrations (see Fig. 1). In addition, these drugs also decrease mucosal edema and are anti-inflammatory because they tend to prevent mediator release from inflammatory cells (Fig. 3). Available bronchodilators include beta-receptor agonists, methylxanthines, and cholinergic antagonists. Beta-receptor agonists are the most effective bronchodilators because they act as functional antagonists of airway constriction, regardless of the stimulus.7 · 24· 6 1. 67 They are most effective in states of bronchoconstriction. Large numbers of beta2-receptors are located on several cell types in the lung, including smooth muscle and inflammatory cells. The interaction between a beta-agonist and receptor causes a conformational change in the receptor and subsequent activation of adenylate cyclase on the inner cell membrane (see Fig. 1). Adenylate cyclase converts ATP to cAMP, which in turn serves as a second messenger for activation of specific protein kinases. The kinases activate the enzymes that cause relaxation of airway smooth muscle. In the inflammatory cell, increased cAMP inhibits mediator release (see Fig. 2). Betareceptors also stimulate secretion of airway mucus, resulting in a less viscous secretion and enhanced ciliary activity. 6• 7• 67 Nonselective beta-agonists such as epinephrine, ephedrine, and isoproterenol are the most important component of therapy of acute respiratory distress in dogs and cats. Epinephrine and isoproterenol

••

•• '-~,,' ···~""

h1stam1ne (H2)

eO

0

/-::

cromogylate (

'

.......... ,

PDE

\

;

t:.2J CD

/

glucocortiCOidS

+cAMP,; fcGMP

/

theophylline

M3

' I

o-.._

phosphoilpases

132

t--- - - -

propranolol

isoproteranol epinephrine ephedrine terbutaline glucocorticoids

nonsteroidal anti-inflammatories I

~"-'-0

0.,__"'a

' PGS

0--__ "'-0 -... AA _..-

0-.._'-0 o-.._'-0...0 '----0

............ LTs PAF

atropine selective anticholinergics

Figure 3. Drugs used to prevent mediator release. Glucocorticoids are among the few drugs that can prevent the activation of phospholipases (mediated by lipocortin) and thus the release of arachidonic acid (AA) metabolites and platelet-activating factor (PAF). Inhibition of prostaglandin (PG) synthesis by nonsteroidal anti-inflammatories may prove beneficial. Mast cell degranulation can be prevented by stimulating alpha-adrenergic receptors, inhibiting calcium influx or phosphodiesterases (POE), or by preventing muscarinic (M3) receptor stimulation. Drugs that block alpha-adrenergic receptors are contraindicated in most respiratory diseases. Solid arrow = induces; broken arrow = inhibits. (From Boothe DM: Feline respiratory pharmacology. In Sheba Symposium Proceedings. Trenton, NJ, Veterinary Learning Systems, 1990, p 32; with permission.)

RESPIRATORY THERAPEUTICS

1239

can be administered parenterally to achieve rapid effects. Isoproterenol and ephedrine can be given orally for chronic therapy. 52 Both epinephrine and ephedrine cause alpha-adrenergic activity, which may cause vasoconstriction and systemic hypertension. Nonselective beta-agonists may cause adverse cardiac effects as a result of beta 1-receptor stimulation. These effects may be problematic in cats suffering from hypertrophic cardiomyopathy. Aerosolization reduces the adverse effects of nonselective beta-adrenergic agonists by increasing beta2 specificity, because only these beta-receptors appear to line the airways. At appropriate doses, beta2-selective agonists are not generally associated with the undesirable effects of beta 1-adrenergic stimulation. However, few of these drugs have been used in small animals. Metaproterenol, a derivative of isoproterenol, and its analogue, terbutaline9 • 52• 61 have been used safely in small animals. Rapid first-pass metabolism of both these drugs results in reduced systemic bioavailability following oral administration; thus, oral doses are considerably higher than parenteral doses. Both drugs, but particularly metaproterenol, can cause beta 1 side effects at high doses. Albuterol and isoetherine are examples of beta2-selective agonists that have been administered by aerosolization in small animals. 9 • 61 Chronic use of beta-adrenergic agonists can result in refractoriness as a result of down regulation (Le., reduced numbers) of beta-receptors. This problem is largely avoided in humans by using proper doses Y Drugs that block beta2-receptors, such as propranolol, are contraindicated in animals with bronchial disease. The methylxanthine derivative, theophylline, has been the cornerstone of long-term bronchodilator in human and veterinary medicine. Its mode of action was originally attributed to inhibition of phosphodiesterase (PDE) and to increased concentrations of cAMP (see Fig. 1). 32 This mechanism is controversial, however, because theophylline is a poor inhibitor of PDE at theophylline concentrations that are in the human therapeutic range of between 10 to 20 J.Lg/mL. PDE exists as various isoenzymes located in different sites within the cell, some of which are inaccessible to drugs.6 • 7 Although theophylline may not affect total PDE, it may inhibit a specific isoenzyme, resulting in bronchodilation. Another possible mechanism is antagonism of the inhibitory neurotransmitter, adenosine, which induces bronchoconstriction during hypoxia. The most likely mechanism by which theophylline induces bronchodilation, however, is through interference of calcium mobilization.6• 7 As with beta-agonists, theophylline is equally effective in large and small airways. Theophylline has other effects in the respiratory system which are important to its clinical efficacy.6 • 7 • 32 In addition to its bronchodilatory effects, it inhibits mast cell degranulation and thus mediator release (see Fig. 2), increases mucociliary clearance, and prevents microvascular leakage. A major advantage of theophylline compared to other bronchodilators is increased strength of respiratory muscles and a corresponding decrease in the work associated with breathing.32 This may be important in animals with chronic bronchopulmonary disease.

1240

BOOTHE & McKIERNAN

Theophylline is one of the few drugs whose pharmacokinetics has been studied in small animals. Regular (immediate release) aminophylline is well-absorbed (bioavailability of at least 90%) following oral administration in both dogs and cats. 48' 49 In dogs, peak plasma drug concentrations for the theophylline base (approximately 8 f.lg/mL following a dose of 9.4 mg/kg) occur 1.5 hours after oral administration. 48 Unfortunately, aminophylline must be administered frequently in dogs (q 6 hours) and cats (q 8-12 hours) in order to achieve plasma theophylline concentrations within the human therapeutic range of between 10 to 20 f.lg/mL. 48' 49 Many slow-release preparations of theophylline have been developed in human medicine to improve the maintenance of therapeutic concentrations while prolonging the dosing interval. The use of several of these preparations have been studied in the dog. 41 The rate of oral absorption of slow-release products in dogs is apparently faster than in humans. The extent of absorption varies with the preparation. In one study, 41 bioavailability of four slow-release preparations administered at a dose of approximately 20 mg/kg ranged from 30% (anhydrous theophylline 24-hr capsules, Theo-24, Searle and Co, San Juan, PR) to 76% (anhydrous theophylline tablets, Theo-Dur, Key Pharmaceuticals, Miami, FL). 41 The least variation in absorption was measured for oxytriphylline enteric-coated capsules (Choledyl-SA, Parke-Davis, Morris Plains, NY) and a 12-hour capsular anhydrous theophylline (Slobid Gyrocaps, Wm. H. Rorer, Ft. Washington, PA). The bioavailability of these two products was approximately 60%. Peak plasma drug concentrations were close to the minimum effective range recommended in humans (10 f.lg/mL) for only three of the slow-release products studied. Predicted fluctuation of plasma drug concentrations during a 12-hour dosing interval was almost 120% for the oxytriphylline product but only 48% for the anhydrous tablet. These data suggest that of the four preparations studied, the anhydrous theophylline tablet (but not the capsule) is preferred in dogs. Although the mean residence time of the slow-release preparations was significantly longer by 1 to 2 hours than the regular preparation, the clinical significance of this difference is questionable. 41 However, the longer release time may allow a dosing interval of 12 rather than 6 hours in the dog for these products. A smaller dose of (immediate release) theophylline is recommended for the cat compared to the dog. 25' 26 This is due to the longer half-life of these products in cats compared to dogs (7.8 vs. 5.7 hours respectively) and to the fact that the elimination rate constant is less in cats than dogs (0.089/hr vs. 0.12/hr48' 49). After intravenous administration, theophylline is characterized by a relatively large volume of distribution (0.7 1/kg in dogs)48 although it is not distributed to all body tissues; the volume of distribution in the cat is 0.46 l/kg.49 Unlike humans, distribution of theophylline is not limited by binding to serum proteins in dogs; serum protein binding is only 10%.55 Because theophylline is not water-soluble, it can only be given 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

RESPIRATORY THERAPEUTICS

1241

theophylline (Table 2). Aminophylline, an ethylenediamine salt, is 78% theophylline, whereas oxytriphylline is 64% theophylline, and glycinate and salicylate salts are only 50% theophylline. Two sustained-release theophylline products have been evaluated in the cat. 25 Once-daily administration has been recommended to achieve the human therapeutic range (Table 2). 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. 26 One disadvantage to the use of the slow-release products in both dogs and cats might be the limited dose sizes that are available. Theophylline is associated with a wide range of adverse effects, including central nervous excitation (manifested as restlessness, tremors, and seizures), gastrointestinal upset (nausea and vomiting), diuresis, and cardiac stimulation (e.g., tachycardia). Use of intravenous aminophylline is limited to patients who have not responded to betaagonist therapy. Rapid infusions or infusions of undiluted drug have been reported to cause cardiac arrhythmias, hypotension, nausea, tremors, and acute respiratory failure .9• 61 Compared to the salt preparations, theophylline is more irritating to the gastrointestinal tract than aminophylline.9• 32• 61 The side effects of theophylline are dose-dependent; to a large degree these may be avoided by appropriate dosing, based on the observation that documented toxicity has only occurred following excessively high drug doses. 56 Therapeutic drug monitoring should facilitate design of proper dosing regimens that avoid toxicity. Dogs are apparently more tolerant of theophylline toxicity than humans. In one study, toxicity manifested as tachycardia, central nervous stimulation (restlessness and excitement), and vomition did not occur until plasma theophylline concentrations reached 37 to 60 f.Lg/mL. Doses of 80 to 160 mg/kg of a sustained release preparation were required to induce toxicity. 56 In cats, concentrations as high as 40 f,Lg/mL were not observed to have induced adverse reactions. 49 In another study, salivation and vomiting were common following administration of more than 50 mg/kg, and seizures occurred at doses greater than 60 mg/kg. 65 Newer methylxanthines such as enprofylline, a drug that does not antagonize adenosine, may eventually replace theophylline as a bronchodilator because of fewer side effects; to date, however, it has not been evaluated in veterinary medicine. 6• 7• 65 The application of therapeutic drug monitoring to guide therapy would assist in identifying the most appropriate dosing regimen. Although a therapeutic range has not been established in small animals, the range recommended in humans can be extrapolated until a specific therapeutic range has been established in dogs and cats. Most laboratories that provide therapeutic drug monitoring are capable of theophylline analysis. Anticholinergic drugs compete with acetylcholine at muscarinic receptor sites and antagonize vagally mediated bronchoconstriction. 30 Anticholinergic drugs have not proven clinically effective for the treatment of bronchial asthma. The site of action of these drugs in the

Table 2. DOSES OF DRUGS USED TO TREAT RESPIRATORY DISEASES Drug BRONCHODILATORS Beta-Agonists* Epinephrine

Dose (mg/kg)

Route

IM, IV, sa

20 j.Lg/kg of 0.01%

sa

0.01 ml/kg of 0.1%

Ephedrine

IM, PO

solution 2-5 mg total (C) 5-15 mg total (D)

Isoproterenol

PO IM, Sa, IV aerosol

0.44 0.1-0.2 mg total 0.5 cc of 1 :200

Metaproterenol

0.5

Terbutaline

PO aerosol aerosol PO PO

lsoetharine

PO aerosol

Frequency (hrs)

solution

6-12 6 4 X 3 6 4 X 3

dilution

Albuterol

30 mint

200 j.l.g:j: 50 (D) 1.25 mg up to 10 kg (D) 2.5 mg up to 25 kg (D) 5.0 mg over 25 kg (D) 0.625 mg total (C) 0.5-1.0 mL of 1 :3 saline solution

8 12 12

8

Anticholinergics Atropine Glycopyrrolate

IV,IM, sa IV, IM, sa

0.02-0.04 0.01-0.02

PAN PAN

Methylxanthines§ Immediate-release products Aminophylline (as the salt)

PO, IV

5 (C) 11 (D) 4 (C) 9 (D)

8-12 6 8- 12 6

PO PO PO PO PO

25 20 25 25 47

24 (in p.m.) 12 24 (in p.m.) 12 12

PO IV, IM IV, IM PO

1-2 2-4 0.2-2.2 0.25-o.S mg total 200 ....g total:j:

6-12 4-6

PO

5 mg total

24 x 4, then weekly x 4

PO PO sa, IM PO PO IM,Sa

1-2 0.22 0.055-().11 0.5-1.0 1-2 0.1

8 6-12

Theophylline base

Sustained-release products Theo-Dur tablets Slo-bid Gyrocaps Choledyl SA tablets (as the salt) ANTI-INFLAMMATORY AGENTS Glucocorticoidsll Prednisolone Prednisolone Na succinate Dexamethasone Triamcinolone Beclomethasone dipropionate inhalant Megestrol acetate ANTITUSSIVE$ Codeine Hydrocodone Butorphanol tartrate Dextromethorphan Morphine

PO

(C) (D) (C) (C) (D)

24 6-8

PAN

6-12 6-8 6-12 Table continued on next page

1242

RESPIRATORY THERAPEUTICS

1243

Table 2. DOSES OF DRUGS USED TO TREAT RESPIRATORY DISEASES Continued Drug

Route

ANTIMICROBIALS Amikacin Amoxicillin Amoxicillin/clavulanic acid Gentamicin Cephalothin Chloramphenicol Enrofloxacin

IM, PO PO IV, IM, IV, IM PO PO

DECONGESTANTS Diphenhydramine Dimenhydrinate Pseudoephedrine

PO PO PO

sa

PO

sa

Dose (mg/kg)

Frequency (hrs)

7-10 10 1G-20 1-2 35 50 mg total 2.5

12 12 12 12-24 12 12 12

2--4 12.5 mg total 15-50 mg total (D) (to max of 4 mg/ kg) 2--4 mg/kg (C)

8 8 8 8-12

*Use cautiously in cats with cardiac disease. tUp to a total dose of 0.5 ml :j:Human dose §Based upon pharmacokinetic studies in dogs and cats where doses are predicted to obtain 1Q-20 f.Lg/ml, the human therapeutic concentration IITaper doses to minimum effective dose IV = intravenous; IM = intramuscularly; sa = subcutaneous; PO = oral; C = cat; D = dog

respiratory tract is controversial. In some studies, bronchodilation is reported throughout the airways in asthmatic human patients and cats, whereas other investigators feel the effects are confined to large airways. 30 The route by which anticholinergics are administered influences their bronchodilatory effects. 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.6.7 Glycopyrrolate is twice as potent as atropine in causing bronchodilation when aerosolized. 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. 48 In the respiratory tract, atropine reduces ciliary beat frequency, mucus 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. 48 Aerosolization of atropine does not reduce the incidence of adverse reactions. Ipratropium bromide is a synthetic anticholinergic and is pharmacodynamically superior to atropine. Although the two drugs are equipotent, ipratropium does not cross the blood-brain barrier. It is not well-absorbed following aerosolization, which limits the likelihood of adverse effects. lpratropium has been studied in the dog30 but not in the cat. Of the anticholinergics studied in dogs, ipratropium appears to cause the greatest bronchodilation (twice as much as atropine) with the least change in salivation. 30 Unlike atropine, it does not alter mucociliary transport

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rates. Glycopyrrolate also can be used as a bronchodilator in small animals. Although its onset of action is slower than that of atropine/· 61 its half-life is 4 to 6 hours, compared to 1 to 2 hours for atropine. The potency following systemic therapy has apparently not been compared between the two drugs, although glycopyrrolate is twice as potent when aerosolized. Systemic side effects of glycopyrrolate are minimal. The lack of clinical efficacy of anticholinergics may reflect nonselective drug-receptor interaction. 6· 7 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 M2receptor stimulation. Drugs specific for M3-receptors may ultimately lead to successful treatment of bronchial disease with anticholinergics.6· 7 Atropine is well absorbed (in humans) following oral administration. In humans, atropine has proven most useful for treatment of chronic bronchitis and emphysema, diseases which are characterized by increased intrinsic vagal tone. 30 However, its adverse effects on respiratory secretions and ciliary activity negate its benefits to bronchial tone during long-term administration in animals. The primary indication of 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. Combination of atropine with either beta-adrenergic agonists or glucocorticoids causes better bronchodilation than either drug alone. 30 Glucocorticoids remain the most effective long-term therapy for feline bronchial asthma because they are both anti-inflammatory and have a "permissive" effect on beta2-receptors. 6· 7· 59 They also are used routinely in the treatment of chronic bronchitis (see the article by Padrid and Amis elsewhere in this issue). Receptor sensitivity to beta-adrenergic drugs is increased, and receptor density in the airways and affinity for beta-adrenergic drugs also may be increased. Potentiation of betaadrenergic activity leads to bronchodilation as well as control of inflammation (see Figs. 1 and 2). Glucocorticoids act by stimulating the formation of lipocortin (lipomodulin, macrocortin, renocortin), a protein that inhibits phospholipase A2 • 6· 7• 31 · 59 By preventing the formation of PGs, LTs, and PAF, glucocorticoids decrease leukocyte accumulation, prevent and reverse increased vascular permeability, and reduce release of additional mediators. Glucocorticoids also induce eosinopenia and lymphopenia, alter macrophage function, modulate the immune system, and inhibit fibroblast growth. 6· 7 • 31· 59 • 77 Thus, glucocorticoids can modify all phases of inflammation important in bronchial disease. The subcellular mechanisms by which glucocorticoids induce their effects depend upon interaction of steroids with specific cytoplasmic receptors. A steroid-receptor complex then enters the cell nucleus, where it activates transcription and the synthesis of messenger RNA coding for formation of the appropriate proteins (e.g., lipocortin). A lag time may occur before the maximum anti-inflammatory effects of glucocorticoids are realized. 3L 77 The anti-inflammatory potency of the

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glucocorticoids varies with the drug. Dexamethasone is 5 to 10 times more potent than prednisolone or triamcinolone. However, it is associated with more adverse reactions, and depending on the formulation, may take longer to be effective77 (dexamethasone phosphate has a faster onset of action). Methylprednisolone is a rapidly acting glucocorticoid; however, its expense tends to limit its use to the preferred drug in the prevention or reduction of oxygen radical formation following reexpansion of atelectatic lungs.42 Glucocorticoids are given intravenously to achieve rapid effects in acute, life-threatening situations, or orally for long-term administration as maintenance drugs. 9 Glucocorticoids are well-absorbed following oral administration. The plasma half-life of the various glucocorticoids ranges from about 1 hour (prednisolone) to 5 hours (dexamethasone). However, the duration of action (biological half-life) of the drugs is much longer. Hydrocortisone and other short-acting glucocorticoids are active for less than 12 hours. Intermediate drugs such as prednisolone and triamcinolone are active for 12 to 36 hours, and long-acting drugs such as betamethasone and dexamethasone are active for more than 48 hours. 77 The adverse effects caused by glucocorticoids have been reviewed. 77 Twice-daily therapy should be used for the initial control of symptoms, particularly in patients that are seriously ill, however, alternate or every third day therapy at the lowest effective dose should be initiated as early as possible. Although cats appear to be less susceptible to the adverse affects commonly associated with long-term glucocorticoid therapy in dogs, alternate-day dosing of short- to medium-acting drugs is recommended in both species. Administration for several months to life may be necessary in some ani!l).als. 9 Glucocorticoids also can be administered by aerosol for rapid, local effects. 36• 40• 77 Triamcinolone acetonide and beclomethasone dipropionate can be aerosolized, 36 although the benefit:risk ratio is greater for the latter. 40 Beclomethasone dipropionate is a glucocorticoid whose anti-inflammatory effects are much greater following aerosolization because it is metabolized to a less active form as it passes through the liver after oral administration. 36 As an aerosol (200 1-1g) it has proven useful for the control of asthma in human patients who respond poorly to other therapy or cannot tolerate systemic glucocorticoid therapy. Although studies have not proven the efficacy of aerosolization in small animals, this route may be indicated for treatment of acute exacerbations of disease or for animals intolerant to systemic maintenance glucocorticoid therapy. Drugs that stabilize mast cells are most effective in syndromes associated with marked mast cell activity. The stabilizing effects of betaadrenergic agonists, methylxanthines, and glucocorticoids on inflammatory cells have been discussed. Although the mechanism of action of cromogylate 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 Fig. 2).6• 7 • 57 At high concentrations, cromogylate inhibits IgE-triggered mediator release from mast cells. 33 Some studies38 suggest that the activation of inflam-

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matory cells other than the mast cells (e.g., macrophages, neutrophils, and eosinophils) is inhibited by cromogylate. Cromogylate is most useful as a preventative prior to activation of inflammatory cells. It is not significantly absorbed following oral administration and is characterized by a short half-life.61 Thus, effective therapy is dependent upon frequent aerosolization, which limits its utility in the treatment of small animal diseases. In human medicine, cromogylate is currently the safest drug used in the management of asthma. 57 It is associated with only minor side effects, and its discovery has revolutionized the treatment of human asthma. Because of its wide therapeutic window and its apparent efficacy in control of many inflammatory cells, its use in the control of small animal bronchial disease warrants further investigation. The use of calcium antagonists for the management of asthma has yet to be identified. 46 Their potential benefits include prevention of mediator release, smooth muscle contraction, vagus nerve conduction, and infiltration of inflammatory cells.23. 46 Most studies indicate that calcium antagonists have only a modest effect on airway smooth muscle contraction. 23• 46 Their effects as anti-inflammatory agents may ultimately prove of greater benefit. The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of respiratory inflammatory diseases needs to be defined.63• 76 Both LTs and PGs are important in the pathophysiology of inflammatory diseases. Although NSAIDs effectively block PGs through inhibition of cyclooxygenase, they do not appear to have any effect on lipooxygenase and therefore the production of LTs. 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. 74 Some studies have shown that LT production increases in response to NSAID therapy, perhaps by providing more AA for lipooxygenase metabolism. 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 canine heartworm disease. 39• 66 Aspirin is the preferred NSAID, because at low doses it irreversibly inhibits TXA2 , an important contributor to the pulmonary arterial vasoconstriction that accompanies thromboembolism. Current efforts in NSAID research are oriented towards identifying drugs that successfully inhibit both arms of the AA metabolic cascade or specific PG or LT inhibitors. The use of selective TXA2 inhibitors in selected feline respiratory diseases is an example. 51 Neither antiserotonins nor antihistaminergics drugs have proven clinically useful in the control of small animal or human respiratory diseases Y· 52• 79 Several observations support their lack of efficacy. Although not proven, the number of histamine receptors located in the airways and the proportion of Hl- to H2-receptors may not be sufficient to induce a response similar to that in disease. Antihistaminergic drugs act to block target receptors from responding to histamine; however, the drugs do nothing to prevent the release of histamine or other mediators from any inflammatory cell. This may be the major reason for the apparent lack of clinical efficacy of antihistaminergic drugs.

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Mediators other than histamine (released during mast cell degranulation) and by other inflammatory cells are often much more potent than histamine.U Finally, blockade of histamine receptors is competitive and can be overwhelmed by high concentrations of histamine. In animals with chronic disease, the use of HI-blockers may be detrimental because of their effects on airway secretions. 8 The role of H2-receptors in bronchodilation, mucus secretion, and inflammation suggests that H2receptor blockers should be used with caution. 8• 15 The clinical efficacy of antiserotonin drugs in the management of feline bronchial qiseases has not been studied despite the apparent sensitivity of feline bronchial smooth muscle to this mediator. 19

Antitussives and Expectorants

The goal of antitussive therapy is to decrease the frequency and severity of cough. Cough suppressants should be used cautiously and are contraindicated if the cough is productive. 71 Irritants, and perhaps chemo- and stretch-receptors initiate the cough reflex. 47• 71 The cough reflex can be blocked peripherally, either by removing the irritant or by blocking peripheral receptors, or it can be blocked centrally at the cough center in the medulla. 69• 71 Whenever possible, the underlying cause should be identified and treated. Bronchodilators may be considered peripheral antitussives because of their effect on airway caliber. It is believed that bronchodilation relieves irritant receptor stimulation induced by the mechanical deformation of the bronchial wall during bronchoconstriction. Ephedrine induces bronchodilation; it is also a decongestant and is a common constituent of over-the-counter cough preparations. Theophylline and isoproterenol are common ingredients found in some preparations. Other peripheral antitussives include mucokinetic agents and hydrating agents. 69 Mucokinetic drugs facilitate the removal of secretions from the respiratory tree and thereby decrease one of the most potent stimulants for coughing. Mucokinesis can be induced by drugs that improve ciliary activity (e.g., beta-receptor agonists and methylxanthines) or by drugs that improve the mobility of bronchial secretions by changing viscosity. Viscosity of bronchial secretions can be decreased by hydration (e.g., sterile water or saline), increasing pH (e.g., sodium bicarbonate), increasing ionic strength (sodium bicarbonate and saline), or by rupture of sulfur (S-S) linkages in the mucus (e.g., acetylcysteine or iodine). Hydrating agents can be administered parenterally (i.e., isotonic crystalloids) or by aerosolization. Home aerosolization can be easily achieved with a humidifier or steamed bathroom. The efficacy of aerosolization in liquefying lower airway secretions is controversiaJ.75 The greatest benefit may occur in the upper airways, but this is very dependent upon particle size and the respiratory breathing pattern. It should be noted that bland aerosols such as water and saline may actually be detrimental to mucociliary function. 75 The efficacy of ionic

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solutions or alkaline solutions compared to water on enhanced mucus mobility is controversial.75 In humans, N-acetylcysteine is the most widely used mucolytic drug. 75, 81 It appears to be efficacious following aerosolization; however, more recently, oral administration has become the preferred route.81 In Europe, the drug is available in solid- and powder-dosing forms. Unfortunately, only the solution, which is unpalatable and malodorous, is approved for use in the United States. Regardless of the route of administration, the mechanism of acetylcysteine involves destruction of the disulfide bonds of mucoprotein by the free sulfhydryl group. Smaller molecules are less viscid and are not able to bind efficiently to inflammatory debris. In addition, N-acetylcysteine serves as a precursor to glutathione, a major scavenger of free oxygen radicals associated with inflammation. The drug also appears to induce respiratory tract secretions, probably via a gastropulmonary reflex. At higher oral doses, acetylcysteine induces vomition. 80 Acetylcysteine is often used in combination with aerosolized antimicrobials because it may improve antibacterial penetration into infected mucus. 81 Acetylcysteine improved gas exchange in a study of dogs with experimentally induced methacholine bronchoconstriction. 73 In humans, acetylcysteine is rapidly absorbed from the gastrointestinal tract and extensively distributed to the liver, kidneys, and lungs, where it may accumulate. It is rapidly metabolized by the liver to cysteine and cystine. 80, 81 The indications for oral acetylcysteine therapy in humans include toxic inhalants (including tobacco smoke), bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, tuberculosis, pneumonia and emphysema, and the adult respiratory distress syndrome. Installation of a 10 to 20% solution also has been used to clean and treat chronic sinusitis. 81 Acetylcysteine therapy is associated with few adverse affects. In humans, doses as high as 500 mg/kg are well-tolerated, 80 although vomition and anorexia can occur. Because it is metabolized to sulfur-containing products, it should be u sed cautiously in animals suffering from liver disease characterized by hepatic encephalopathy. Aerosolization of N-acetylcysteine can cause reflex bronchoconstriction owing to irritant receptor stimulation and should be preceded with bronchodilators. Direct instillation, via bronchoscopy, has been recommended to assist in the removal of bronchial (mucus) plugs. Expectorants such as potassium iodide are common ingredients in over-the-counter cough preparations. They are not antitussives but are often used as adjuvants for the management of cough by facilitating removal of the inciting cause. Expectorants increase the fluidity of respiratory secretions through several mechanisms. Bronchial secretions are increased by vagal reflex following gastric mucosa irritation (iodide salts) and are increased directly by volatile oils or through sympathetic stimulation. Although the combination of expectorants with antitussives may seem irrational, the antitussive drugs in these combination products do not appear to prevent stimulation of the cough reflex induced by liquified secretions, The expectorant mechanism of action of guai-

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fenensin, a common ingredient of over-the-counter cough preparations, is unknown. It may be ineffective at the doses used in cough preparations. 62 Centrally active antitussives are classified as narcotic and nonnarcotic drugs. 69 Narcotic antitussives depress the cough center sensitivity to afferent stimuli. However, they can be associated with strong sedative properties, as well as with constipation when administered chronically. Morphine, codeine, and hydrocodone can be used for cough suppression in both dogs and cats (Table 2). Hydrocoaone is more potent and causes less respiratory depression than codeine. The narcotic agonist/antagonist, butorphanol tartrate, is a potent antitussive when given orally or parenterally in dogs and cats. 34 An advantage of this preparation is that it is not a scheduled drug. Dextromethorphan is a nonnarcotic opioid commonly found in over-the-counter cough preparations. It is used in small animals with minimal sedation. Its antitussive efficacy is reportedly equal to codeine, and it can be used safely in cats. Studies in humans have shown that the combination of dextromethorphan with a bronchodilator is superior to dextromethorphan alone. 72 Noscapine is. a nonaddictive opium alkaloid (benzylisoquinolones) that has antitussive effects similar to codeine. 14 Its use in small animals appears to be limited. Respiratory Stimulants

Respiratory stimulants or analeptics cause central nervous stimulation; excitation of the respiratory center is a secondary effect. Because they act centrally, they also may increase basal metabolism and thus oxygen utilization. Central nervous system stimulants include the methylxanthines, ephedrine, and beta2-agonists, as previously discussed. Doxapram is also a central nervous system stimulant that induces respiration. Response to doxapram is short-lived; the respiratory center becomes refractory to its effects with repeated administration. Narcotic antagonists should be used to reverse respiratory depression induced by opiates; tolazoline and yohimbine can be used to reverse sedative affects induced by alpha2-agonists. Although naloxone is a pure antagonist and therefore the most effective reversal agent for narcotic-induced respiratory depression, butorphanol and buprenorphine are unscheduled agonists/antagonists that also can reverse the sedative and respiratory depression induced by opiates. An advantage to these latter drugs is their ability to maintain or induce some degree of analgesia.

Decongestants

The indication for decongestants include sinusitis of allergic or viral etiologies and reverse sneezing or other complications of postnasal drip. Intermittent topical therapy is preferred to facilitate breathing and

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reduce the volume of nasal discharge. Antihistaminergic (e.g., dimenhydrinate and diphenhydramine) and alpha-adrenergic drugs (e.g., ephedrine, pseudoephedrine, and phenylephrine) are effective decongestants that can be given orally or topically. To avoid possible systemic effects, however, topical therapy of alpha-adrenergics is preferred. The decongestant activity of ephedrine is partially dependent upon norepinephrine release. Prolonged use may deplete storage granules, and the animal may become refractory to its effects. In addition, rebound congestion may result from secondary beta-adrenergic effects as receptors upregulate.

AEROSOLIZATION AS A ROUTE OF DRUG ADMINISTRATION

The primary indications for aerosolization are to directly deliver drugs to the respiratory tract and to facilitate liquefaction and mobilization of respiratory secretions. The benefits of direct drug delivery include assurance that target tissues receive high concentrations while systemic exposure and potentially toxic reactions are avoided (e.g., aminoglycosides and anticholinergics). In addition, hepatic first-pass metabolism following oral administration is circumvented, which serves to prolong the pharmacologic effect of selected drugs (e.g., betaadrenergic agonists and beclamethasone). Inhalation therapy in small animals has been recently reviewed. 2 1 The successful patient response to aerosolized drugs is more likely a reflection of adequate drug delivery rather than a function of drug efficacy. Predicting the amount of drug delivered to the target tissue is not possible in small animals. Factors determining the amount of drug administered via aerosolization include the aerosolizer used and the particle size it generates, technique of delivery (i.e., mask versus endotracheal tube and nose versus mouth), flow rate of the delivery gas, and patient factors such as anatomy of the respiratory tract and respiratory rate and pattern. 14 • 58 The optimum particle size for particle (and drug) deposition in the trachea is 2 to 10 f.l, that in peripheral airways is 0.5 to 5.0 f.l. Less than 10 to 20% of aerosolized drug probably reaches the tracheobronchial tree, and even less will reach the peripheral airways. With progression of chronic disease, therapy may become less effective as the respiratory pattern of the patient becomes shallow and rapid: depth of aerosol penetration decreases and more drug is deposited in upper airways. Administration of an aerosol by mask reduces drug delivery to the tracheobronchial tree, because particles are deposited in the nasal turbinates and oropharynx. The utility of aerosolization may be further limited because of stimulation of irritant receptors and reflex bronchoconstriction. 45• 81 Resistance by the animal to aerosolization (e.g., during application of a face mask) may further exacerbate respiratory distress and interfere with drug administration. Animals should be either pretreated with a beta-adrenergic bronchodi-

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lator 10 minutes prior to aerosolization, 36 or a bronchodilator can be included in the aerosolized medicament (e.g., 100 mg aminophylline 68). In humans, aerosolization is a well-established route of administration for bronchodilators and anti-inflammatory agents. 75 In veterinary patients, aerosolization is more commonly used for administration of mucolytics (e.g., saline) and, on occasion, antibiotics. Indications for aerosol therapy include chronic bronchial diseases and infections of both lower and upper airways. Drugs for which aerosolization have been recommended are listed in Table 3. ANTIMICROBIAL THERAPY

Infections of the lower respiratory tract should be considered as serious. Infections of the tracheobronchial tree may be less serious but can be important contributors to more serious diseases such as asthma. 53 Although infections of the sinuses are seldom life-threatening, they are difficult to treat and are usually associated with manifestations undesirable to the owner and pet. Important considerations to be made when selecting and using an antimicrobial in the treatment or prevention of small animal respiratory infections include (1) the causative organism and its antimicrobial susceptibility; (2) drug distribution to the site of infection within the respiratory tract; (3) the mechanism of action of the drug, particularly as it relates to bactericidal versus bacteriostatic effects; (4) chronicity of the disease; (5) potential toxicity of the drug; and (6) convenience of administration. 50 Pasteurella sp and Moraxella sp (probably a nonpathogen) are the most common organisms isolated from the respiratory tract of cats with bronchial disease. 53 In dogs, Bordetella bronchiseptica is the most common organism associated with tracheobronchial diseases; Bordetella, Escherichia coli, Pseudomonas spp, Klebsiella spp, and Streptococcus zooepidemicus Table 3. DRUGS ADMINISTERED VIA AEROSOLIZATION Bronchodilators49 · 58 Isoproterenol lsoerthraine Albuterol Atropine• Glycopyrrolate• Glucocorticoids Beclomethasone22• 35· 36 Triamcinolone35

Mucokinetics•· 70 Water Saline Bicarbonate N-acetylcysteinet Antimicrobials Gentamicin"· 78 Amikacin" Kanamycin 70 Polymyxin Bt" Amphotericin Bt 70 Nystatint70 Others Alcohol42

*In combination with other bronchodilators. tDrug-induced bronchoconstriction may be severe.

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are common primary pathogens in pneumonia. Other pathogenic bacterial microorganisms associated with respiratory disease in small animals include Staphylococcus spp and alpha- and beta-hemolytic streptococcus. 4' 20 The presence of aspiration pneumonia or pulmonary abscesses should prompt the clinician to consider anaerobic bacteria as a pathogen in infectious diseases. 13 The role of bacteria in chronic bronchial disease of dogs and cats is controversial. 6°Consideration must be made between colonization of bacteria from infection. Selection of the appropriate antimicrobial is best made on the basis of culture and sensitivity testing of isolates obtained from the trachea or lower airways. Although bactericidal drugs are preferred, the clinician must appreciate that no drug is bactericidal if adequate tissue concentrations are not achieved. In general, distribution to the lower airways (lung parenchyma) is adequate to excellent for most drugs. There is some concern regarding the degree of penetration of various antibiotics into bronchial secretions, 64 which may help to explain the efficacy of aerosolized versus parenteral antibiotics that was reported by Bemis in his studies 10 on experimentally induced Bordetella tracheobronchitis in the dog. Use of lipid-soluble drugs may be preferred (e.g., quinolones, chloramphenicol) for upper airway infections. Beta-lactam antibiotics are excellent first-choice drugs for the treatment of most bacterial infections. The bactericidal aminopenicillin, amoxicillin, is well-absorbed orally, is distributed to the lungs, and is characterized by a broad spectrum of activity. Drug distribution into inflamed sinuses is probably adequate. The addition of the betalactamase protectant, clavulanic acid, increases the efficacy of amoxicillin against both gram-negative (including Pasteurella sp and Bordetella) and gram-positive anaerobes and aerobes. The combination drug is well-tolerated in both dogs and cats. First-generation cephalosporins (e.g., cephalothin, cephalexin, and cefaclor) are also excellent choices for gram-negative organisms, although they may not be as effective for the treatment of anaerobic infections. Third-generation cephalosporins and extended spectrum penicillins (e.g., ticarcillin) can be used for serious or life-threatening gram-negative infections. The fluorinated quinolones (enrofloxacin) are very well-distributed to the lungs and are bactericidal towards gram-negative aerobes (including Pseudomonas spp) as well as Mycoplasma sp, an organism that may be associated with bronchial diseases. 53 Enrofloxacin has been used by the author (DMB) for the treatment of chronic sinusitis in cats. Cats appear to tolerate the drug well even if it is administered for several weeks. Complete remission has been reported, although not confirmed, in two cats using enrofloxacin, and another cat has responded to 3-week cycles of enrofloxacin followed by the combination of amoxicillin/clavulanic acid. The use of ciprofloxacin, a human fluorinated quinolone, is questionable in veterinary medicine, because it is a major metabolite of enrofloxacin. The aminoglycosides also are effective in treating life-threatening or complicated gram-negative infections. Their distribution to the lungs is adequate, although not as great as for the quinolones. Aerosolization of aminoglycosides can enhance their therapeutic efficacy, especially in

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the treatment of Bordetella- associated tracheobronchitis and Pseudomonas infections. 10• 64• 75 Absorption of gentamicin (up to 7.5 mg/kg in 3 mL saline) appears to be negligible in dogs following aerosolization by mask.68 Amikacin and kanamycin kinetics following aerosolization apparently have not been studied in the dog, but it is unlikely that they will be systemically absorbed. Aerosolization of polymyxin B was associated with marked bronchoconstriction in humans/4 but bronchoconstriction was not reported in a study of polymyxin B aerolosization in dogs. 10 In the authors' opinions, systemic antimicrobial th~rapy is indicated in concert with aerosolization. If safe, the antimicrobial being aerosolized should be given systemically to generate bactericidal concentrations in the lung parenchymal tissues. Alternatively, a synergistic drug combination (e.g., aminoglycosides and penicillins) can be selected. Although sulfonamides and sulfonamide-trimethoprim combinations are distributed well to respiratory tissues, it has been suggested that the emergence of resistance by veterinary strains of several organisms may decrease the utility of these drugs. 2° Chloramphenicol, on the other hand, is a good first-choice antimicrobial for selected, uncomplicated respiratory tract infections. However, the drug is bacteriostatic and is not well-tolerated in the cat. Treatment of pulmonary dimorphic fungal diseases (e.g., blastomycosis, histoplasmosis, coccidiodomycosis) is difficult. Amphotericin B and ketoconazole generally are effective against these organisms. Because the effects of amphotericin B are more rapid in onset, its use is usually preferred for life-threatening, severe infections. The combination of amphotericin B and ketoconazole has been shown to be effective in the treatment of canine blastomycosis while decreasing host toxicity. 43 Both amphotericin B (5 mg/day) and nystatin (50,000 U) have been administered as an aerosol in humans, although their use was associated with marked bronchoconstriction. 75 No data are available on the use of these drugs as aerosols in veterinary medicine. Newer antifungal agents that have been used systemically in small animals include itraconazole and fluconazole; enilconazole has been used topically. Itraconazole and fluconazole are superior to ketaconazole in the treatment of all dimorphic fungi. An added advantage of these drugs is their enhanced tissue penetrability. Fluconazole is available as a human preparation in the United States, but itraconazole is not, although clinical trials in small animals are currently underway. Enilconazole is not intended for systemic use, but it has been used topically for the treatment of nasal aspergillosis in dogs and cats. 7° Caution is recommended with its use in cats; deaths have been reported despite topical therapy. (Brent Herrig, Pitman Moore, personal communication, 1991) SUMMARY: PHARMACOLOGIC CONTROL OF BRONCHIAL DISEASES

Acute respiratory distress caused by bronchial disease should be handled as a medical emergency and initially treated with bronchodi-

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lators. Beta2 -adrenergic agonists are preferred, but nonselective agonists can be just as effective in critical cases. Parenteral rather than oral administration assures the most rapid onset of action. Aerosolization should not replace parenteral administration, but it can be used in concert with it 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. 9 The addition of atropine or glycopyrrolate may facilitate bronchodilation. Exacerbation of hypoxia is a complication of bronchodilator therapy due to drug-induced pulmonary vasodilation/1 and the potential for ventilation-perfusion mismatching necessitates administration of humidified oxygen. Glucocorticoid therapy should be initiated in conjunction with bronchodilators in cats with "asthma" or in dogs whose respiratory disease is associated with inflammatory cells, particularly eosinophils or mononuclear cells. Rapidly acting drugs such as prednisone sodium succinate should be administered upon presentation and again at 4 to 6 hours. 9 ' 52 Alternatively, dexamethasone or dexamethasone phosphate, because of its anti-inflammatory potency, may be administered. The hydration status of the patient should be assessed upon presentation and corrected if indicated. However, overzealous fluid therapy, especially in cats, can prove detrimental and should be avoided. Oral bronchodilator and glucocorticoid therapy can begin when the patient is stabilized. Long-term therapy with bronchodilators may not be necessary in cats with bronchial disease when a good response to glucocorticoid therapy has been obtained. On the other hand, the potential adverse effects of long-term glucocorticoid therapy may be avoided if bronchodilator therapy alone is sufficient to control the clinical symptoms of bronchial disease. Oral theophylline is the bronchodilator most commonly used for long-term bronchodilator therapy in dogs and cats, 9 , 52' 61 although terbutaline can be used as an alternative, particularly in animals refractory to theophylline. Sustained-release theophylline products (see Table 2) are recommended, because they require less frequent dosing and therefore should be associated with better owner compliance. 25, 41 Alternating between theophylline and beta-agonists may prevent the incidence of refractoriness due to downregulation of beta-receptors. If glucocorticoids are used chronically, prednisolone (or prednisone) is the most commonly preferred maintenance drug, although triamcinolone is acceptable. Long-term glucocorticoid therapy may not be indicated in dogs unless the disease is associated with eosinophilic or mononuclear infiltrates. A 2- to 3-week trial period is indicated to establish efficacy and need. 4 Maintenance doses should be slowly tapered to a minimum effective dose 1 to 2 weeks after therapy is started. Glucocorticoid therapy should be maintained for a minimum of 1 to 2 months. Complete cessation of therapy may be possible in selected cases, although (seasonal) relapses may occur. Repositol forms of glucocorticoids should not be administered owing to the risk of exacerbation of disease. 9 Remission of clinical signs appears to be more

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difficult in animals that have received these drugs. Intermittent high doses of intravenously administered or aerosolized glucocorticoids, and particularly beclomethasone dipropionate, in conjunction with oral maintenance glucocorticoids can be used to treat animals whose disease becomes exacerbated. 9• 31 Alternatively, megastrol acetate has been recommended in lieu of intermittent high doses of glucocorticoids in cats with refractory asthma. 9 The routine use of antimicrobial agents for the treatment of chronic respiratory diseases is controversial. Distinction between infedjon and colonization should be made whenever possible. Selection of the antimicrobial agent should be based upon culture and sensitivity testing. The role of antitussives in the treatment of diseases depends upon the character of the cough and is usually limited to cases in which the cough is nonproductive. Inflammation and infection can result in mediator release and coughing without an increase in bronchial secretions. In the case of a productive cough, coughing may actually be encouraged through the use of expectorants, mucolytics, and physiotherapy.

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Address reprint requests to Dawn Merton Boothe, DVM, MS, PhD Department of Veterinary Physiology and Pharmacology Texas A&M University College of Veterinary Medicine College Station, TX 7784,3- 4466