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.^1,2 Its fibers are responsible for the baseline tone of mild bronchoconstriction that characterizes the normal respiratory tract through M₃ muscarinic receptors. The effects are balanced by bronchodilation resulting from β₂-receptor stimulation.^3–5, In contrast, α-adrenergic stimulation can contribute to bronchoconstriction.^2,4,6 A third, largely understood nervous system, referred to as the nonadrenergic, noncholinergic system or the purinergic system, also innervates bronchial smooth muscle.^1,7 This system mediates bronchodilation by way of vagal stimulation. The afferent fibers of this system are probably irritant receptors, and although the neurotransmitter has not yet been conclusively identified, vasoactive intestinal peptide has been implicated in the cat.^8,9 Malfunction of this system has been associated with bronchial hyperreactivity, which often characterizes asthma.⁷

The intracellular mechanisms that transmit signals from the nervous system to smooth muscle depend in part on changes in the intracellular concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Figure 20-1). The effects of these two secondary messengers are reciprocal such that the increased intracellular concentration of one is associated with a decreased concentration of the other. Cyclic AMP-induced bronchodilation is decreased by α-adrenergic stimulation and increased by β₂-receptor stimulation.³ In contrast, cGMP-induced bronchoconstriction is increased by stimulation of muscarinic (cholinergic) and, indirectly, histaminergic receptors (see Figure 20-1). The relative sensitivity of bronchial smooth muscle to histamine-induced and acetylcholine-induced bronchoconstriction varies with the location and species.^5,10,11 Peripheral airways in dogs are more susceptible than in cats to acetylcholine; feline airways, in general, are more sensitive to acetylcholine and serotonin than histamine.¹² Smooth muscle receptors are also susceptible to stimulation by a variety of chemical mediators (see Figure 20-1), which may also modulate cAMP and cGMP.^13–15

Figure 20-1 Factors determining bronchial smooth muscle tone. Reciprocal changes in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) determine muscle tone. Contraction occurs when cAMP levels are decreased by events such as α-adrenergic 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 β-adrenergic or histamine (H₂) receptor stimulation counteract muscle contraction. Inhibition of phosphodiesterase (PDE) also causes increase cAMP. Although the effects of most inflammatory mediators are best counteracted by preventing their release, several drugs may be used to antagonize smooth muscle contraction regardless of the etiology. LTC, Leukotriene C; LTD, leukotriene D; PAF, platelet-activating factor; PGD₂, prostaglandin D₂, PGF₂, prostaglandin F₂; TXA₂, thromboxane.

Control of bronchial smooth muscle tone is very complex and depends on input from sensory receptors. At least five types of sensory receptors have been identified in cat lungs, all of which can be classified as irritant (or mechanoreceptor), stretch, or J-receptors.⁷ All appear to be innervated by the parasympathetic system. Irritant receptors, located beneath the respiratory epithelium, occur in the upper airways² and, in cats, as far peripherally as the alveoli.¹ Physical, mechanical, or chemical stimulation of these receptors results in tachypnea, bronchoconstriction, and cough. As reviewed by Canning,^7a rapidly adapting receptors (RARs) terminate in or below the epithelium primarily of intra-pulmonary, but to some degree, extra-pulmonary airways. They can adapt within 1 to 2 seconds to changes in airway mechanics and are subject to activation by multiple stimuli, including chemical mediators. In contrast, slowly adapting receptors (SARs) may be responsible for physiologic responses (i.e., termination of inspiration and initiation of expiration). SARS centrally inhibit respiration and decrease airway smooth muscle tone. However, they may facilitate cough. Cats have few SARS but many RARs.^7a C-fibers represent the majority of fibers innervating the airways and lungs. They are physiologically similar to nociceptors of other tissues. They appear to synthesize neuropeptides (e.g., substance P) that influence the central and peripheral nerve terminals. Mediators stimulating C-fibers vary: in dogs, pulmonary subtypes do not (but bronchial subtypes do) respond to histamine, and in other animal models, they do not respond to serotonin or adenosine. C-fibers regulate airway defense reflexes, interacting with RAR, although the scientific description of these fibers is not clear. C-fibers and RARS interact with the spinal cord through central sensitization. Subsequent heightened reflex responsiveness may occur; tachykinins (including substance P) appear to play a role in hyperreflexia, an effect prevented by neurokinin receptor antagonists. Convergence of vagal afferents in the nucleus of the solitary tract may explain in part the close relationship between vomiting and coughing. Receptors also converge in the ventral respiratory column of the medulla. Airflow velocity appears to be the most critical factor determining stimulation of irritant receptors in the upper airways.¹ Airway constriction sufficient to cause airflow velocity to exceed a specific threshold results in a vagally mediated cough reflex and bronchoconstriction. Airways can also be occluded by mucus and edema or by chemical mediators released during upper airway infections.⁷

In addition to the cough receptors, afferent nerves, efferent nerves and effector muscles, the cough reflex also consists of a poorly defined cough center.

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.² The mucociliary apparatus (Figure 20-2) is the first major defense and consists of the ciliary lining of the tracheobronchial tree and the fluid blanket surrounding the cilia. Nervous innervation to the cilia has not yet been identified. Although ciliary activity increases with β-adrenergic stimulation, this may simply reflect the sequelae of β-adrenergic stimulation on respiratory secretions.¹⁶ Two types of secretions form the fluid blanket of the respiratory tract.¹⁷ 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 and serves to trap foreign materials inspired with air. The synchronous motion of the cilia causes the cephalad movement of the mucous layer and any trapped materials.

Figure 20-2 The mucociliary apparatus represents the first line of defense for pathogens entering the respiratory tract. Cilia are bathed in a water or sol layer. When the cilia beat in synchrony, the movements send forward (orally) the mucoid or gel layer that lies on top of the cilia. Materials trapped in this layer also move forward to be either swallowed or expectorated.

Changes in the viscoelastic properties of mucus such that it becomes either too watery or too rigid will result in mucus transport that is less than optimal.² Mucus released by goblet cells results from direct irritation² and is not amenable to pharmacologic manipulation. Surface goblet cells, which are uniquely prominent in feline bronchioles,¹⁸ increase in number with chronic disease. Submucosal glands of the bronchi secrete both a serous and a mucoid fluid. The secretions tend 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.² Glycoproteins increase the viscosity of the secretions, providing protection and lubrication. Infection and chronic inflammatory diseases can have a profound effect on respiratory secretions. The glycoprotein component tends to be replaced by degradative products of inflammation such as DNA and actin.¹⁷ Goblet cell numbers increase with a subsequent increase in the viscosity of respiration secretion. Parasympathetic, cholinergic stimulation increases mucus secretion, whereas β-adrenergic stimulation causes secretion of mucus, electrolytes, and water.^2,16

The second major component of the pulmonary defense system is the respiratory mononuclear phagocyte system. In cats, calves, pigs, sheep, and goats, this includes both alveolar macrophages and the pulmonary intravascular macrophages (PIMs).¹⁹ The PIMs are resident cells that are characterized by phagocytic properties and thus cause the release of inflammatory mediators. The clearance of blood-borne bacteria and particulate matter in these species is accomplished by PIMs rather than hepatic Kupffer cells and splenic macrophages as in most other species.¹⁹ The pharmacologic significance of the mononuclear phagocyte system reflects their role in inflammation (Figure 20-3; see also Figure 20-1). A number of preformed (e.g., histamine and serotonin) and in situ (e.g., prostaglandins, leukotrienes, and platelet-activating factor [PAF]) mediators are released by inflammation cells.^13–15 Each is capable of inducing a variety of adverse effects that tend to decrease airway caliber size: edema, chemotaxis, increased mucus production, and bronchoconstriction (Table 20-1). The involvement of PIMs in both experimental and natural respiratory diseases of animals suggests that release of chemical mediators from these cells may be important in the pathogenesis of bronchial diseases.

Figure 20-3 The formation of mediators important in the pathogenesis of respiratory disease. Leukocytes and other cells release arachidonic acid metabolites and platelet-activating factor (PAF) after activation of phospholipases by a variety of stimuli. Mast cell degranulation induced by both immune and nonimmune stimuli is also accompanied by arachidonic acid metabolism as well as by the release of preformed mediators that 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 α-adrenergic receptor stimulation. Drugs used to prevent mediator release include glucocorticoids, which are one of the few classes of drugs that can prevent activation of phospholipases (mediated by lipocortin) and thus release of arachidonic acid metabolites and PAF. Inhibition of prostaglandin synthesis by nonsteroidal antiinflammatory drugs may prove beneficial but also may lead to increased formation of leukotrienes by providing more arachidonic acid. Leukotriene actions can be blocked either by leukotriene receptor antagonists or by blockade of leukotriene receptors. Mast cell degranulation can be prevented by stimulation of β-adrenergic receptors, inhibition of calcium influx or phosphodiesterase (PDE), or prevention of M₃ receptor stimulation. Drugs that block β-adrenergic receptors are contraindicated in most respiratory diseases. DAG, diacylglycerol; IP₃, inositol triphosphate; PIP₂, phosphatidylinositol; PKC, protein kinase C; PLC, phospholipase C; PLA₂, phospholipase A₂.

Table 20-1 Inflammatory Mediators and Their Proposed or Known Role in Asthma

Histamine

Histamine is a vasoactive amine stored in basophils and mast cells. Airway mast cells are located primarily beneath the epithelial basement membrane in dogs.²⁴ Histamine produces a variety of effects (see Table 20-1) by interacting with specific receptors on target cells.^12,42 At least four histamine receptors have been identified,^5,29,43,44 two of which have been found in the trachea of the cat.^5,6 Interaction with the H₁ receptor causes an increase in intracellular calcium, and ultimately in cGMP (see Figure 20-3).²⁹ Histamine also stimulates cholinergic receptors in the airway.^24,29 Histamine causes constriction in both central and peripheral airways in dogs and cats.^12,24 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.²⁹ Lack of clinical response to H₁-receptor antagonists, however, led to the realization that other factors are more important. In contrast to H₁ receptors, stimulation of H₂ receptors causes an increase in cAMP and bronchodilation.²⁹ Thus antihistamine drugs that block H₂ receptors may be contraindicated in asthma. Some studies have suggested that a defect in H₂ receptors may contribute to airway hyperreactivity.²⁹ Finally, recent evidence suggests that histamine regulates both T_h1 and T_h2 cells. Further, cells perpetuating the allergic response may be influenced by histamine through H₄ receptors located on eosinophils, basophils, mast cells, and dendritic cells.⁴³

Histamine contributes to bronchial occlusion by mechanisms other than bronchoconstriction. Mucous secretion is mediated via H₂ receptors and by secretion of ions and water via H₁ receptors.²⁹ Microvascular leakage resulting from contraction of endothelial cells also follows H₁-receptor stimulation.²⁹ Histamine is chemotactic to inflammatory cells, particularly eosinophils and neutrophils. Interestingly, histamine stimulates T-lymphocyte suppressor cells by way of H₂ receptors,⁵ a function that also may be depressed in human patients with asthma.²⁹ Histamine also has a negative feedback effect on further histamine release mediated by IgE.²⁹ Both of these latter effects are mediated by H₂ receptors and would be inhibited by H₂-receptor antagonists.⁵

Serotonin

Serotonin (5-hydroxytryptamine [5-HT]) is released during mast cell degranulation.²⁹ 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 after aerosolization or intravenous administration.¹² Constriction may reflect interaction with serotonin receptors or enhanced release of acetylcholine. Serotonin may also cause profound vasoconstriction of the pulmonary vasculature and microvascular leakage.²⁹

Prostaglandins and Leukotrienes

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 (see Figure 20-3). 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 actions of various synthetases and isomerases on the endoperoxides result in the final PG products, including PGE₂, PGF_2α, PGD₂, prostacyclin (or PGI₂), and thromboxane (TXA₂). The amount of each PG produced in the lung varies with the cell type and species. The effects of the various PGs tend to balance one another. PGD₂, PGF_2α, and TXA₂ cause bronchoconstriction, whereas PGE₁ and, to a lesser extent PGI₁, cause bronchodilation.^1,29 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.²⁹ Thromboxane A₂ appears to be the predominant AA metabolite produced by feline lungs,⁴⁵ although other PG mediators are also important.⁴⁵

The role of LTs in atopy has been increasingly scrutinized in recent years. Lipoxygenases catalyze the conversion of AA to hydroperoxyeicosatetraenoic acid (HPETEs), which are further metabolized to several hydroxy acids (HETEs) and LTs (Chapter 29). Eosinophils have been known to be preferentially activated 5-lipoxygenase²⁹; selective activation of lipoxygenase by antigenic challenge yields subsequent formation of the cysteinyl LTs (cystLTs: LTB₄ C₄, and D₄), recognized as the components of slow reactive substance of anaphylaxis.²⁹ However, both intermediate and end products of lipoxygenase are active in the respiratory tract (see Table 20-1).²⁹ Among these mediators are some of the most potent inflammagens known. For example, 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 mucous release in the dog but appear to be less potent in the cat.²⁹ In humans airway allergen challenge increases LTs in urine and bronchoalveolar lavage (BAL) fluid with asthma and nasal secretions with allergic rhinitis.³⁵ Increases in LTs in plasma, BAL fluid, or urine of challenged cats is controversial, although cats experimentally infected with dirofilariasis likewise exhibited increased plasma as well as BAL fluid cysLT concentrations (unpublished data). The cysteinyl LTs exert biologic effects through cysLT1 and cysLT2 receptors.³⁵ Binding by LTs to eosinophilic cysL1 receptors (particularly LTD4) results in chemotaxis and prolonged survival, effects that are blocked by LT-receptor antagonists.³⁵ Further evidence suggests that cysteinyl LTs are also involved in the initial systemic atopic response that is mediated from the bone marrow.^35,46

Platelet-Activating Factor

PAF is also formed after activation of phospholipase A₂ in cell 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.^22,23 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. PAF has been implicated as the cause of the sustained bronchial hyperresponsiveness that characterizes asthmatics.²³ The role of PAF in feline and canine respiratory diseases has not been addressed. Eosinophils are, however, a major cell type associated with feline bronchial disease and some canine diseases, and it is likely that PAF is an important inflammatory mediator.

Neuropeptides

Several chemicals stimulate release of inflammatory neuropeptides from sensory neurons enervating smooth muscles. Cells stimulating neuropeptide release include macrophages, T-cells, eosinophils, and mast cells; example neuropeptides include substance P and, to a lesser degree, calcitonin gene-related peptide and neurokinin A.⁴⁷ As with other inflammatory mediators, neuropeptides are associated with vasodilation, increased permeability and mucus production, as well as histamine release.

Cytokines

The role of cytokines in the coordination and persistence of chronic airway inflammation is integral and, not surprisingly, very complex. The integrated nature of their actions renders them simultaneously ideal as targets of drug therapy but potentially a source of adverse events should therapy be successful. Four cytokine classes have been proposed: lymphokines, chemokines, and proinflammatory and antiinflammatory cytokines (see Table 20-1). The role of lymphokines was largely addressed with the discussion of T_h cell role in atopy. Initiation of T_h2 cells is not clear, but appears to involve presentation of restricted antigens in the presence of IL-4 and IL-10. Perhaps the most notable lymphokine of asmtha is IL-5.⁴⁸ Recruitment of eosinophils into the lungs—the hallmark of asthma—is IL-5 dependent. However, IL-5 also is integral to the differentiation, proliferation, and maturation of eosinophil progenitor cells in the bone marrow before recruitment into the lung.

Chemokines are cytokines that attract inflammatory cells, including eosinophils, monocytes, and T-lymphocytes. Two groups have been described based on proximity of cysteine residues to one another: CXC or α chemokines (separated by an amino-acid) and CC or β-chemokines (no separation; see Table 20-1). Chemokines exert their effects through rhodopsin-like G protein–coupled receptors (referred to as CXC-R or CC-R). Because certain cells express selected receptors, pharmacologic therapy increasingly will be designed to be selectively antiinflammatory.³¹ Among the cells influenced by chemokines are eosinophils, which in turn release more chemokines. Among the most notable drugs targeting proinflammatory chemokines, and particularly their transcription, are glucocorticoids (see Chapter 30). Newer therapies take advantage of the presence of antiinflammatory cytokines; indeed, glucocorticoids facilitate restoration of antiinflammatory cytokines such as IL-10.

Communication Molecules: Adhesion Molecules and Integrins

Communication between cells is facilitated by adhesion molecules that interact, by way of ligand binding, with receptors on the surface of inflammatory cells known as integrins. Integrins are present on many cells, with receptor specificity occurring for selective cells. Integrins are absent on T_h1 cells but are particularly prevalent on T_h2 cells, mast cells, and eosinophils. Interaction between adhesion molecules and integrins promotes migration, activation, and increased survival of inflammatory cells. Drugs that target eosinophilic integrins (α4β1 and 7) offer a possible mechanism whereby selective control of inflammation may limit side effects.⁴⁹

Bronchodilators and Anti-Inflammatory Drugs

Because of a shared intracellular mechanism of action, most drugs that induce bronchodilation also reduce inflammation. Bronchodilators reverse airway smooth muscle contraction by increasing cAMP, decreasing cGMP, or decreasing calcium ion concentration (see Figure 20-1). In addition, these drugs also decrease mucosal edema and are antiinflammatory because they tend to prevent mediator release from inflammatory cells (see Figure 20-3). Rapidly acting bronchodilators include β-receptor agonists, methylxanthines, and cholinergic antagonists.

β-Receptor Agonists

β-receptor agonists (Figure 20-4) are the most effective bronchodilators because they act as functional antagonists of airway constriction, regardless of the stimulus.^22,50,51 Few β-agonists generally have been sufficiently studied in animals to describe pharmacokinetics or pharmacodynamics.

Figure 20-4 Structures of selected beta-adrenergic drugs used to induce bronchodilation. Epinephrine is the least and albuterol or terbutaline the most selective for β-2 receptors. Most β-adrenergic drugs are present as enantiomers, as is demonstrated here for albuterol.

Large numbers of β₂-receptors are located on several cell types in the lung, including smooth muscle and inflammatory cells.³ The receptor is linked to a stimulatory guanine nucleotide-binding protein (G protein). The interaction between a β-agonist and receptor causes a conformational change in the receptor and subsequent activation of adenylyl cyclase on the inner cell membrane (see Figure 20-1).⁵² Adenylate cyclase converts adenosine triphosphate to cAMP, a second messenger for activation of specific protein kinases that ultimately activate enzymes responsible for airway smooth muscle relaxation. β-receptor agonists are most effective in states of bronchoconstriction. Additional effects of β-adrenergic receptors include increased mucociliary clearance, which reflects a decrease in fluid viscosity (presumed to reflect movement of chloride and water into the lumen) and an increase in ciliary beat frequency. Additionally, they inhibit cholinergic neurotransmission, enhance vascular integrity, and inhibit mediator release from mast cells, basophils, and other cells (see Figure 20-3).^22,23,51,52 Eosinophil, but not lymphocyte, numbers appear to decrease, but long-term inflammation does not appear to be affected,⁵² probably because inflammatory cell β receptors are rapidly desensitized (discussed later). As such, long-term β-adrenergic use should be accompanied by antiinflammatory therapy.⁴¹

As with many membrane-associated receptors, high doses or repeated exposure to β-adrenergic agonists results in desensitization.⁵¹ The mechanism depends on the duration of therapy. Initial drug–receptor interaction causes phosphorylation, which interferes with G proteins. Longer exposure causes receptors to internalize such that they are not accessible by the drug; continued exposure causes downregulation of receptor mRNA such that the number of receptors is actually reduced.⁵² Reduction develops over several weeks before stabilizing. Desensitization may contribute to acute exacerbations of bronchoconstriction associated with long-acting β-adrenergics. Bronchodilation will be less in the desensitized airway necessitating increased treatment frequency. However, frequent use may mask clinical signs associated with uncontrolled inflammation and care must be taken that long-acting β-adrenergics are not used instead of antiinflammatory therapy. Despite these shortcomings, β-adrenergics are the most the most effective bronchodilators.

The β-adrenergic agonists (see Figure 20-4) can be given by a variety of routes. In humans inhalation is preferred because it is equally effective to parenteral administration and is safer. However, drug delivery to the peripheral airways must be addressed as much as possible.

Nonselective β-Agonists

The nonselective β-agonists (i.e., capable of both β₁ and β₂ stimulation) such as epinephrine, ephedrine, and isoproterenol are used for acute and chronic therapy of respiratory diseases. Epinephrine and isoproterenol can be administered parenterally to achieve rapid effects, and drugs that can be given orally for chronic therapy include isoproterenol and ephedrine.⁶ Both epinephrine and ephedrine cause α-adrenergic activity, which may cause vasoconstriction and systemic hypertension and may contribute to airway constriction.⁴ Nonselective β-agonists may cause adverse cardiac effects as a result of β₁-receptor stimulation. Aerosolization reduces the adverse effects of nonselective β-adrenergic agonists by increasing β₂ specificity, because only these β-receptors appear to line the airways.

β₂-Selective Agonists

At appropriate doses, β-selective agonists are not generally associated with the undesirable effects of β₁-adrenergic stimulation. The more commonly used β-agonists are categorized as to their duration of action: intermediate (3 to 6 hours) and long-acting (>12 hours). The two long-acting bronchodilators, salmeterol and formoterol, both have extended side chains, are highly lipophilic, and are characterized by high affinity for the β-2 receptors. However, the long duration of salmeterol reflects binding to a specific site within the receptor, whereas that for formoterol reflects gradual release from the cell membrane lipid.⁵² The long-acting nature of bitolterol reflects its pulmonary metabolism to an active metabolite. However, it has a rapid onset of action and generally is used for acute therapy.

Short-acting drugs that have been used in animals include albuterol, metaprotereno (a derivative of isoproterenol), and its analog terbutaline.⁴¹ Metaproterenol is less β-2 selective than other agents and more apt to cause cardiac stimulation.⁵² Therefore repetitive use should be pursued only cautiously. Albuterol, metaproterenol and terbutaline are available as oral preparations; each has been used apparently safely in dogs. Rapid first-pass metabolism reduces systemic bioavailability after oral administration; as such, oral doses are greater than parenteral doses. These drugs, but particularly metaproterenol, can cause β₁ side effects at high doses. Clenbuterol, also a β-2 selective agonist, is approved for use in horses. Although manufactured as the racemic mixture, pharmacologic effects are largely limited to the L-isomer.⁵³ Tachycardia occurs in dogs at 0.4 mg/kg, which is only half of the therapeutic dose recommended in horses. Further, cardiac necrosis occurs at 2.5 mg/kg, which represents only a threefold increase over the equine therapeutic dose. Consequently, use of clenbuterol in dogs may not be prudent. Albuterol and isoetharine are examples of β₂-selective agonists that have been administered by aerosolization to small animals.³⁰ Salbutamol is frequently used as a rescue bronchodilator in humans.⁵⁴

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.

Methylxanthine Derivatives

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.

KEY POINT 20-6

Oral bioavailability of slow-release theophyllines may markedly vary among products and patients, contributing to toxicity or therapeutic failure.

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

Anticholinergic Drugs

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