The afferent arc of the cough reflex receives input from sensory nerves in the bronchial and tracheal airways. Airway irritation and inflammation stimulate the afferent nerves, which in turn activate the cough center located in the medulla oblongata.

The antitussive drugs directly depress the cough center in the medulla. The site of action may be either μ- or κ-opiate receptors (discussed in Chapter 13). Opiate drugs that act on these receptors are effective, but it is not simply because they produce sedation (Morjaria et al., 2012). Either of the opiate receptors may be responsible for the action because both butorphanol (κ-receptor agonist) and codeine or morphine (µ-receptor agonists) can suppress cough (Takahama and Shirasaki, 2007; Gingerich et al., 1983; Christie et al., 1980; Morjaria et al., 2012), but naloxone is capable of antagonizing this effect.

There may be a nonopiate mechanism for some antitussives as well (Morjaria et al., 2012). For example, dextromethorphan is an opiate derivative, but does not have activity at opiate receptors and may bind to sites in the brain that are distinct from opiate receptors. It is continues to be marketed as an over-the-counter (OTC) antitussive for people – apparently based on early clinical trials. Its mechanism is unknown. The neurokinin receptor (NK) may play a role in antitussive activity of such nonopiates. This mechanism has not been well characterized (Takahama and Shirasaki, 2007), but is discussed further with the NK-1 receptor antagonist drugs below. Beta-2 receptor agonists (β₂) will suppress cough in some animals. The effect of these drugs is mediated via bronchodilation. These drugs will be discussed in Section Bronchodilator Drugs (β-Adrenergic Receptor Agonists).

Morphine and derivatives have opiate-receptor–mediated effects, but also are effective as antitussives. Morphine is a natural derivative of one of the alkaloids of opium (Chapter 13). Morphine is the prototype of an opiate (narcotic) analgesic with good binding affinity for the µ- and κ-opiate receptors. Morphine can be administered at low doses that produce antitussive effects without causing analgesia and sedation. The antitussive dose has been reported to be approximately 0.1 mg/kg, q 6–8  h. Morphine is not regularly used as an antitussive because of the side effects and potential for abuse and addiction in humans. Oral formulations of morphine do not have good systemic absorption in dogs (see Chapter 13).

Codeine phosphate and codeine sulfate are found in many preparations including tablets, liquids, and syrups. There are over 50 different combinations and preparations of codeine. However, codeine oral absorption in dogs is low and inconsistent.

Codeine has analgesic effects that are approximately 1/10 that of morphine. Studies in people have shown little benefit from codeine for cough suppression, but the small amount of codeine metabolized to morphine may produce an antitussive effect. In dogs codeine administered orally attains systemic levels of only 4% (KuKanich, 2010), but it is possible that other metabolites may be responsible for the antitussive effect. Despite the occasional use in dogs, the efficacy for treating cough has not been studied. It is available as 15, 30, and 60-mg tablets and oral syrups (2 mg/ml). In some states (regulated by local regulations), and some countries, codeine in antitussive formulations may be obtained without prescription.

In people, the side effects of codeine at antitussive doses are significantly less than those experienced with morphine. The potential for addiction and abuse is considerably lower. Important side effects include sedation and constipation.

Hydrocodone is similar to codeine in mechanism of action, but it is more potent. Hydrocodone is combined with an anticholinergic drug (homatropine) in the preparation Hycodan^®, which has been prescribed often for small animals. Pharmacokinetic studies have shown that is absorbed orally in dogs but there is conflicting evidence in dogs on the metabolism to hydromorphone (Benitez et al., 2015). It is possible that the antitussive effect is produced by a different metabolite. Nevertheless, some veterinarians consider it their first drug of choice for symptomatic treatment of cough in dogs. The anticholinergic component (homatropine) is added to discourage abuse rather than for a respiratory indication. Oral doses administered to dogs are approximately 0.22–0.25 mg/kg, q 6–8 h (approximately 1 tablet per 20 kg).

Dextromethorphan is not a true opiate because it does not bind µ- or κ-opiate receptors, but studies in people have supported its antitussive effects. More recent investigations have questioned the antitussive properties of OTC formulations.

Dextromethorphan is the D-isomer of levorphan (the L-isomer, levorphan is an opiate with addictive properties, but the D-isomer is not). Dextromethorphan produces mild analgesia and modulates pain via its ability to act as an NMDA (N-methyl D-aspartate) antagonist, but this is unrelated to the antitussive action (Pozzi et al., 2006).

Butorphanol is an opioid agonist–antagonist that has been used both as an analgesic and antitussive. It has been a potent antitussive with clinical studies that support its use in dogs (Gingerich et al., 1983; Christie et al., 1980). High doses may induce side effects such as sedation.

Butorphanol is poorly bioavailable because of oral first-pass metabolism. Therefore, in dogs the oral dose is higher (0.55 to 1.1 mg/kg) than the IV or SC dose (0.05 to 0.1 mg/kg). It is administered as frequently as needed to control cough – usually every 6 to 12 hours. In clinical studies the peak effect was rapid after the injectable formulation. After oral administration, the maximum effects were observed for 4 hours but persisted for up to 10 hours in dogs (Gingerich et al., 1983). By contrast, codeine’s effect in dogs is much shorter. It is available as 1, 5, and 10-mg tablets and an injectable solution.

Tramadol is an inexpensive oral drug used for analgesia. It possesses opiate, serotonin, and α₂ activity. (The pharmacology of tramadol is discussed in more detail in Chapter 13). The active metabolite has opiate activity and is believed to be responsible for most of the analgesia. This drug also has antitussive properties and appears to be well tolerated in dogs, and it is not a controlled substance. However, efficacy for treating cough in dogs has not been evaluated. The recommended oral dose is 5 mg/kg, every 6 hours, but this has not been tested for antitussive efficacy (KuKanich and Papich, 2004b).

Bronchial smooth muscle is innervated by β₂-adrenergic receptors. Stimulation of β₂ receptors leads to increased activity of the enzyme adenylate cyclase, increased intracellular cyclic adenosine monophosphate (cyclic-AMP), and relaxation of bronchial smooth muscle (see Chapter 7).

The β agonists discussed below should be used for short-term relief of bronchospasm. They should be avoided for long-term use as repeated administration may diminish the response because of a change in receptors after prolonged exposure. The receptor changes during chronic administration are a result of down-regulation and desensitization. Concurrent use of corticosteroids may attenuate the desensitization. For management of airway diseases, other drugs (e.g., corticosteroids) can be used for long-term maintenance, and β agonists used short term during acute exacerbations of bronchoconstriction.

Inhaled aerosols of β₂ agonists are important drugs for treatment of acute bronchospasm in human patients with asthma or allergic bronchitis. Nebulization is the process of creating small droplets of a drug that can be inhaled into the airways. Nebulized agents are delivered via jet nebulizers, ultrasonic nebulizers, and metered-dose inhalers. (Inhalation products are also discussed with the corticosteroids in Section Inhaled Corticosteroids.) Several metered-dose inhalers are marketed for this use in people, such as albuterol (Ventolin^®), bitolterol (Tornalate^®), terbutaline (Brethaire^®), and pirbuterol (Maxair^®).

The use of these aerosols has become more common in animals because adapters are available to allow for use by animal owners. In horses, masks are available that allow a metered-dose inhaler to be used (Derksen et al., 1996; Tesarowski et al., 1994). These devices are available for dogs, cats, and horses. For example, the AeroKat^® chamber has also been used to deliver these medications to cats.

The most common adverse effects from β agonists involve the cardiovascular system (tachycardia) and skeletal muscles (muscle tremors) (Fox and Papich, 1989). Cardiac effects (rapid heart rate, palpitations, tremors) can be prominent with β₁ agonists and can be produced by β₂ agonists at high doses. When high doses of β agonists have been nebulized to horses, muscle twitching, sweating, and excitement have occurred. β₂-receptor agonists also inhibit uterine motility and should not be used late in pregnancy. However, these drugs have been used therapeutically for this purpose in situations in which it may be desirable to inhibit uterine contractions to delay labor. High doses of β₂ agonists also can produce hypokalemia.

As noted above in the clenbuterol section, these drugs also have properties that affect skeletal muscle. These drugs have been abused in humans and animals for their muscle-building properties. High doses can cause muscle twitching and hyperthermia.

Regular administration of β agonists can produce drug tolerance, which is a loss in the sensitivity of β-adrenergic receptors owing to down-regulation of receptors. This effect occurs when β-adrenergic drugs are administered regularly for several weeks. Therefore, it is best to rely on these drugs intermittently and allow drug-free breaks in treatment. In animals, the best use of these drugs is for short-term treatment for acute exacerbations of bronchoconstriction and corticosteroids can be used to decrease inflammation for long-term management.

Cromolyn inhibits mast cell release of histamine, leukotrienes, and other substances from sensitized mast cells that cause hypersensitivity reactions, probably by interfering with calcium transport across the mast cell membrane. It has no intrinsic bronchodilator action.

Cromolyn has been used as an aerosol for treating recurrent airway obstruction (RAO) in horses (Thomson and McPherson, 1981) and has improved some clinical measurements in horses with respiratory disease (Hare et al., 1994). It has been administered via inhalation once daily for 1–4 days, which will provide a therapeutic effect for several days. In one report, nebulization of 80 mg once daily for 1–4 days prevented signs of heaves in horses for up to 3 weeks. The recommended dose is 80 mg of a 0.02% solution from an ultrasonic nebulizer, or 200 mg from a jet nebulizer (Couëtil et al., 2016). However, other studies have produced conflicting results. The primary drawback is the route of administration and timing. To be effective, it must be administered before the horse is exposed to the allergen (prophylactically). This agent has its effects primarily on mast cells (Hare et al., 1994). Because airway diseases in animals may have neutrophilic or eosinophilic inflammation, this treatment may have limited impact unless mast cells contribute substantially to the disease.

The methylxanthines are classified as CNS stimulants, but they have a variety of pharmacological effects on various organ systems (Weinberger and Hendeles, 1996). The methylxanthines relax bronchial smooth muscle and produce antiinflammatory effects that are unrelated to the bronchodilating properties. In addition, there are nonrespiratory effects of methylxanthines, which include CNS stimulation, urinary diuresis (mild), as well as cardiac stimulation (mild).

Theophylline drug plasma assays are available in many laboratories. When theophylline is used long term, monitoring is recommended to establish the optimum dose. In dogs and cats, the accepted therapeutic plasma concentration is 10 to 20 µg/ml, but these values were extrapolated from human studies. In animals, we aim for plasma concentration greater than 10 µg/ml (usually 10–20 µg/ml) for clinical effects. Plasma concentrations greater than 15 µg/ml have been reported to cause clinical adverse effects in horses.

Antiinflammatory action may occur in patients at concentrations that are below the concentrations usually considered for bronchodilation. For example in people, a concentration of 6.6 µg/ml theophylline caused a reduction in activated eosinophils (Sullivan et al., 1994). In the review by Barnes (2003) the antiinflammatory effects are reported to occur in people at concentrations of 5–10 µg/ml, which is approximately half of the concentration needed to produce bronchodilation.

Mild adverse effects include gastrointestinal signs, which includes nausea and vomiting. More important adverse effects of theophylline are attributed to cardiac stimulation. In this regard, theophylline is more potent than either caffeine or theobromine. The cardiac effects may be summarized as increased heart rate, increase in myocardial contractility (mild), improved right and left systolic function, vasodilation (mild), and diuretic (weak). At high doses, cardiac arrhythmias are possible.

CNS stimulation is more likely from caffeine than theophylline or theobromine. However, at high doses, theophylline also can affect the CNS. These are reported less frequently from theophylline use in small animals than in humans, but they can be common in horses. The CNS effects can be characterized by increased alertness, agitation, nervousness, increased activity, and convulsions at high doses. At high doses there is decreased cerebral blood flow (26%), which may be related to the incidence of seizures.

Caution is advised after rapidly intravenous dosing as adverse effects have been described when theophylline is rapidly administered intravenously in horses and dogs. If the drug is administered orally, high peak plasma concentrations are less likely (Munsiff et al., 1988).

Theophylline relies on hepatic metabolism by cytochrome P450 enzymes for clearance. Therefore, interactions are possible when other drugs are administered that affect these enzyme systems. The metabolism of theophylline may be inhibited by erythromycin, fluoroquinolone antibiotics (for example, enrofloxacin), and cimetidine. The metabolism may be induced by rifampin and phenobarbital, which may necessitate increasing the dose if these drugs are used together. Activated charcoal will increase the clearance of theophylline and other methylxanthines and is useful for treatment of a toxic overdose.

Theophylline has been used for the treatment of both cardiac and respiratory diseases in dogs. Some veterinarians have included theophylline in regimens for the management of congestive heart failure, although this has become an outdated treatment because of availability of newer cardiac drugs. (Note that pimobendan and milrinone, discussed in Chapter 21, are also phosphodiesterase inhibitors.) Theophylline is also employed for the management of intrathoracic collapsing trachea and various forms of bronchitis.

Older sustained-release tablets have been studied in dogs and cats (Koritz et al., 1986; Dye et al., 1989). However, these formulations were recently discontinued and the dose recommendations no longer apply. Decreased availability of older sustained-release formulations led to the use of sustained-release tablets and capsules. These have now become unavailable to many pharmacies, which has led to a decline in use. If available, oral administration of sustained-release formulations in dogs at a dose of 10 mg/kg, q 12 h will produce concentrations in dogs within a range considered to be therapeutic (Bach et al., 2004). Studies in cats (Guenther-Yenke et al., 2007), showed that a dose of 100 mg per cat of the tablet, or 125 mg/cat of the capsule (approximately 15 or 19 mg/kg, respectively) every 24–48 hours maintained plasma concentrations in a range considered to be therapeutic.

Administration of theophylline to horses has a narrow therapeutic index and it is considered less effective than other agents (Box 48.1). Adverse effects have prevented more common use and, because of the CNS stimulant effect, it is banned from performance horses.

Despite the risk of adverse effects and questionable efficacy, theophylline has been considered for management of RAO in horses. Studies in the 1980s (Button et al., 1985; Errecalde et al., 1984; Ayres et al., 1985; Ingvast-Larsson et al., 1989; Kowalczyk et al., 1984) summarize the pharmacokinetics and effects of theophylline in horses. Oral doses are preferred to avoid the high concentrations from injections. A loading dose of 12 mg/kg has been followed by maintenance doses of 5 mg/kg, every 12 hours. One study demonstrated that affected horses showed decreased wheezing, decreased respiratory effort, and an improvement in PCO₂ and blood pH following theophylline administration. However, none of the horses returned to normal. There also is evidence that phosphodiesterase inhibitors are not effective in horses with recurrent airway obstruction (Lavoie et al., 2006). Theophylline produces a positive cardiac chronotropic effect and a weak diuretic effect in horses. Toxicosis can occur from large doses and doses administrated rapidly intravenously. Toxic signs include tremors, excitement, tachycardia, and sweating.

Although there is little clinical experience with the use of theophylline in cattle, experimental evidence suggests that it is a poor bronchodilator in this species (McKenna et al., 1989).

Pearson and Riebold (1989) compared the effects of atropine, isoproterenol, and theophylline in horses with RAO (Box 48.1). Atropine at doses of 0.02 mg/kg, IV was better at relieving some signs of RAO (reduction in intrathoracic pressure for example) than either theophylline or isoproterenol. Isoproterenol was more effective in this study than theophylline.

If anticholinergic drugs are administered, the quaternary amines such as glycopyrrolate (Robinul-V^®), propantheline, (ProBanthine^®), and isopropamide should be used instead of atropine because quaternary amines are less likely to cross the blood–brain barrier and CNS side effects will be minimized. (This property is discussed in Chapter 46.)

Atropine is acceptable for short-term use and a 5 mg IV dose has been used as a response test in horses suspected of presenting with RAO. Ipratropium bromide (Atrovent^®) is a quaternary amine that is an effective bronchodilator in human asthmatic patients. It is administered as an aerosol and is the first anticholinergic drug to be approved as a bronchodilator. Since ipratropium is not absorbed from the airways, it is described as a “topical form of atropine.” It has been administered to horses for treatment of RAO and produced effects for 6 hours at a dose of 2 µg/kg.

The cardiac effects and inhibition of gastrointestinal function prohibit long-term use of atropine. The topical drugs (e.g., ipratropium) have less systemic effects. Because these agents are used in horses, the most important concern is the effect on intestinal motility. Atropine should not be used repeatedly in horses because it can cause ileus. N-butylscopolammonium bromide has become preferred for the acute treatment of bronchoconstriction in horses because when administered once (0.3 mg/kg IV), it was shorter acting, and produced fewer adverse effects, including those on the heart and intestine, than atropine (de Lagarde et al., 2014).

The pharmacology of the glucocorticoids was discussed in more detail in Chapter 29, with some of the immunosuppressive properties discussed in Chapter 45. In patients with inflammatory airway diseases, glucocorticoids have potent antiinflammatory effects on the bronchial mucosa. Glucocorticoids bind to receptors on cells and inhibit the transcription of genes for the production of mediators (cytokines, chemokines, adhesion molecules) involved in airway inflammation (Rhen and Cidlowski, 2005). In horses with RAO, administration of oral dexamethasone in combination with feeding changes decreased the gene expression of proinflammatory cytokines in bronchoalveolar cells (DeLuca et al., 2008). A decrease in the synthesis of inflammatory mediators such as prostaglandins, leukotrienes, and platelet-activating factor caused by glucocorticoids also may be important (Barnes, 1995a, 1989, 2006). Glucocorticoids have a more pronounced effect on neutrophils and eosinophils than mast cells, which is important because neutrophilic and eosinophilic inflammation has been cited as an important component of equine and feline airway disease (Reinero, 2011; Trzil and Reinero, 2014; Mazan, 2015; Couëtil et al., 2016; Pirie, 2014). Glucocorticoids also enhance the action of adrenergic agonists on β₂ receptors in the bronchial smooth muscle, either by modifying the receptor or augmenting muscle relaxation after a receptor has been bound. Corticosteroids may prevent down-regulation of β₂ receptors. Glucocorticoids and theophylline used together appear to be synergistic (Barnes, 2003).