Respiratory Drug Therapy

Chapter 151


Respiratory Drug Therapy




Drugs are the “go to” therapy for respiratory diseases for most clinicians and are the focus of this chapter. However, other therapies can be equally or more important and should not be overlooked: for example, oxygen supplementation; physical therapy; maintenance of hydration, healthy body weight, and oral hygiene; improvement of environmental air quality (reduction of irritants); stenting procedures; and surgical intervention. Drugs used to treat respiratory conditions fall into several classes, including antitussives, bronchodilators, antiinflammatory drugs, expectorants and mucolytic drugs, decongestants, and antimicrobials. This chapter provides a brief overview of therapeutic agents in these classes. Dosage regimens not listed in this chapter are found in the Appendix of Commonly Used Drugs at the back of this book or in a separate formulary (Papich, 2011). The discussion of specific antimicrobial treatments is limited because the area is too large for exhaustive coverage in this brief chapter.



Antitussive Drugs


Cough suppression does not produce a cure and should not be used as primary treatment for undiagnosed respiratory disease because it may mask clinical signs and allow disease to progress unchecked. Cough suppression is rarely indicated for cats, in which the primary disease (often bronchitis) should be addressed directly. However, it may provide relief in dogs with acute airway diseases, may lessen tracheal irritation associated with repetitive and prolonged coughing episodes, and is a primary treatment for dogs with tracheobronchomalacia (tracheal and/or bronchial collapse) that do not have an active inflammatory or infectious component to their disease.


Unfortunately, except for early studies of butorphanol, there are no reliable clinical trials in small animals that have evaluated the effectiveness of antitussive agents, and the mechanism of action of antitussive drugs is not completely understood. There are both opiate and nonopiate antitussive drugs, although growing evidence suggests that the nonopiate drug dextromethorphan is less effective than once thought.


The most commonly used and seemingly most effective antitussives are opiate derivatives. These drugs directly depress the cough center in the medulla, possibly through either mu or kappa opiate receptors. There is evidence that either receptor may be responsible inasmuch as butorphanol (a kappa receptor agonist) and codeine or morphine (mu receptor agonists) can suppress cough (Gingerich et al, 1983; Takahama and Shirasaki, 2007), and naloxone is capable of antagonizing this effect. It has also been proposed that sedative effects produced from opiates may contribute to the reduced coughing.


The β2-receptor agonists suppress cough in some animals. The effect of these drugs is mediated via bronchodilation, and discussion of these agents is presented later.



Codeine (Methylmorphine)


Morphine is not regularly used as an antitussive because of its side effects and potential for abuse, but its derivatives are commonly used. Codeine phosphate and codeine sulfate are found in many preparations, including tablets, liquids, and syrups. Codeine has analgesic effects that are approximately one tenth those of morphine but antitussive potency similar to that of morphine. Although codeine administered orally to dogs attains systemic levels of only 4% (KuKanich, 2010), other metabolites may be responsible for the antitussive effect. Despite its occasional use in dogs, its clinical efficacy for treating cough has not been studied. Important side effects include sedation and constipation. In people, the side effects of codeine at antitussive dosages are significantly less than those experienced with morphine. The potential for addiction and abuse is also considerably lower than for other opiates.



Hydrocodone


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 for small animals. Pharmacokinetic studies have shown that it is absorbed following oral administration in dogs, and active metabolites may persist for several hours. Some veterinarians consider it their drug of first choice for symptomatic treatment of cough in dogs. The anticholinergic component (homatropine) is added to discourage abuse rather than for a respiratory indication. Oral dosages administered to dogs are approximately 0.22 to 0.25 mg/kg, q6-8h (~1 tablet per 20 kg). Higher dosages may be needed for patients with tracheobronchomalacia that have been treated with this drug for years. The side effect of sedation becomes the limiting factor, because it affects quality of life.


Formulation note: Hycodan is formulated as 5 mg of hydrocodone plus 1.5 mg homatropine. Only in Canada is hydrocodone (5 mg) available without an anticholinergic added. Hydrocodone (5 mg) and acetaminophen (500 mg) are combined in a tablet (Vicodin) and used for analgesia, which is safe for dogs but not for cats because of cats’ sensitivity to acetaminophen toxicity.



Dextromethorphan


Routine use of dextromethorphan is not recommended in dogs, and its efficacy in people has been recently questioned. Further, pharmacokinetic studies in dogs indicate that dextromethorphan does not attain effective concentrations after oral administration (KuKanich and Papich, 2004). Dextromethorphan caused adverse central nervous system (CNS) effects after intravenous injection and vomiting after oral administration. Even after intravenous administration, concentrations of the parent drug and active metabolite persisted for only a short time after dosing. Therefore, routine use in dogs is not recommended until more data are available to establish safe and effective doses.




Bronchodilators


The primary indication for bronchodilators is treatment of cats with bronchial inflammation, regardless of cause (e.g., allergic, infectious, or idiopathic bronchitis), in which bronchoconstriction can be a major feature of disease. Dogs with bronchial disease rarely develop clinically apparent bronchoconstriction but may show clinical improvement when given these drugs because of effects beyond bronchodilation. Bronchodilators are sometimes used in cats or dogs in respiratory distress that have primarily parenchymal disease, such as aspiration pneumonia, because airways are often concurrently affected. A therapeutic trial is indicated to be sure that clinical status is not worsened in patients in distress. Bronchodilators have effects on vascular smooth muscle, as well as airway smooth muscle, and may interfere with the matching of perfusion to ventilation.



β-Adrenergic Receptor Agonists


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 (cAMP), and relaxation of bronchial smooth muscle. In addition to bronchodilation, other effects may contribute to efficacy. Activation of the β-receptors on mast cells produces a stabilizing effect (inhibition of mediator release), even though there is little effect on other inflammatory cells. Also, there is some evidence that β-adrenergic receptor agonists increase mucociliary clearance in the respiratory tract.


Epinephrine is the prototype of adrenergic agonists and it has been used in emergency situations, but repeated and prolonged use for airway disease would be detrimental. Instead, β2-receptor–specific agonists are preferred. Terbutaline is most often used and is similar to isoproterenol in its β2 activity, but it is longer acting (6 to 8 hours). It may be injected subcutaneously or intravenously to relieve an acute episode of bronchoconstriction. It is also available in oral formulations. Dosages for this and other bronchodilators can be found in the appendix. Albuterol (called salbutamol in some countries) is similar to terbutaline. It can be given orally as a tablet or liquid up to four times daily.



Inhalant Administration: Nebulizers and Metered Dose Inhalers


Inhaled aerosols of β2-agonists, particularly albuterol, are important drugs for treatment of acute bronchospasm (asthma attacks) in cats, usually seen in association with idiopathic, allergic, or infectious bronchitis but also occasionally with aspiration pneumonia and during performance of tracheal wash, bronchoscopy, or bronchoalveolar lavage. The β-agonists can be administered topically to the airways via inhalation using wet nebulization or metered dose inhalers (MDIs). Nebulization is the process by which small droplets are created from solutions of drug, resulting in a visible fog. To be effective, the particles must be within a size range that can reach the affected airways. Nebulization of a drug solution is carried out by jet or ultrasonic nebulizers. For best results, the drug is administered via a snug anesthetic face mask attached to connecting tubes. Delivery of drug by nebulizer is time consuming, usually requiring 10 to 15 minutes per treatment every 4 to 8 hours, not including time for setup. One method for nebulization in veterinary medicine is administration of drug directly into a small incubator or oxygen cage for treatment of fractious or easily stressed patients, although this does result in a damp patient. Bacterial colonization of the nebulization apparatus and solutions should be prevented, and instructions for care, cleaning, and disposal of parts should be followed carefully.


Administration of bronchodilators by MDI, delivered using a dedicated spacer, has largely replaced nebulization of albuterol in human medicine. Although scientific studies are limited, several reports in the literature and years of clinical experience have made the use of MDIs commonplace in veterinary medicine. It is critical that a spacer specifically designed for MDIs be used. Old practices such as using toilet paper rolls greatly diminish the already small percentage of drug that actually reaches the lower airways. In addition, the spacer must have a sensitive valve that will open during the relatively low pressures generated by tidal respirations of a cat or small dog. Spacers that have been used successfully in veterinary patients are the AeroKat and AeroDawg and OptiChamber devices. The AeroKat and AeroDawg spacers include a face mask, whereas an anesthetic face mask must be attached to the OptiChamber. The inconvenience of adapting a face mask may be worthwhile in some patients to achieve the best fit. Cleaning instructions provided by the manufacturer should always be followed. The primary bronchodilator used in the United States is albuterol (Ventolin). Administration of this drug by inhalation is indicated only for short-term use to treat acute exacerbations of bronchoconstriction.



Adverse Effects of and Tolerance to β-Agonists


The most common adverse effects of β-agonists occur at high doses and affect the cardiovascular system (tachycardia) and skeletal muscles (muscle tremors or twitching). The muscle activity, in turn, can produce hyperthermia. The β2-receptor agonists also inhibit uterine motility and should not be used late in pregnancy. High doses of β2-agonists also can produce hypokalemia.


Inhaled administration of albuterol by MDI can induce airway inflammation. Its use is best limited to treatment of acute bronchoconstriction, such as in exacerbations of feline bronchitis or respiratory distress accompanied by clinical signs supporting the presence of obstructive disease (marked expiratory effort, wheezing, and/or hyperinflation).


Regular administration of β-agonists can cause 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 (as rescue inhalation therapy) and allow drug-free breaks in treatment. Regular use of corticosteroids can mitigate the loss of β-receptor sensitivity caused by chronic use of β-agonists.



Methylxanthines (Xanthines)


The methylxanthines include theobromine, caffeine, and theophylline. Once a mainstay in the treatment of human asthma and chronic obstructive pulmonary disease, theophylline use in people has diminished because of a high incidence of adverse effects, primarily nausea, and the availability of better-tolerated and more effective drugs. However, its therapeutic effectiveness has led to ongoing development of more targeted phosphodiesterase 4 inhibitors, which are hoped to have fewer side effects.


In dogs and cats, theophylline is used for the treatment of bronchitis and may be of benefit to some dogs with tracheobronchomalacia. Unlike in people, the drug is well tolerated in these species, and oral dosing is convenient. As for most respiratory therapies for dogs and cats, well-controlled clinical studies of efficacy have not been performed. Anecdotally, marked clinical improvement is seen in some patients. In cats, the bronchodilatory effects may predominate. In dogs, it is quite possible that other effects contribute to improvement in clinical signs.


The methylxanthines relax bronchial smooth muscle and hence are known as bronchodilators. However, there is evidence that they have antiinflammatory effects, including possible enhancement of the activity of corticosteroids, which may occur at lower concentrations than those producing the bronchodilating effects. As described for terbutaline, there is evidence that methylxanthines improve mucociliary clearance in dogs. Nonrespiratory effects of methylxanthines include CNS stimulation, urinary diuresis (mild), and cardiac stimulation (mild).


The cellular basis of action of the methylxanthines is still not completely understood, although adenosine receptor antagonism is thought to play a role in humans because adenosine triggers bronchoconstriction in asthmatic individuals. Another probable action is inhibition of phosphodiesterase types 3 and 4. (Other drugs such as pimobendan and sildenafil target more specific inhibition of phosphodiesterase enzymes 3 and 5.) Phosphodiesterases are enzymes that catalyze the breakdown of cAMP and cyclic guanosine monophosphate to inactive products. Inhibition of the phosphodiesterase enzyme increases intracellular concentrations of the cyclic nucleotide cAMP. In turn, cAMP inhibits the release of inflammatory mediators from mast cells, has antiinflammatory effects, and produces bronchial smooth muscle relaxation.



Theophylline Formulations


Theophylline has been available in several formulations, including injectable aqueous solutions, elixirs, and immediate-release and extended-release tablets and capsules. All available formulations are designed for people; there are no veterinary preparations. Pharmacokinetic studies have been performed on both immediate-release and sustained-release formulations in dogs and cats that help to guide dosing; however, the sustained-release products that have been tested are not currently on the market. Because there are no approved animal formulations, the veterinarian is left to prescribe any formulation available. Our recommendation is to begin dosing using the guidelines listed in this chapter and to be prepared to increase or decrease the dose, or dosing interval, based on the patient’s clinical response and tolerance. Dose adjustments are best made by measuring the patient’s plasma/serum concentration and adjusting the dose to an appropriate plasma/serum concentration, as well as observing for adverse effects of this drug. Immediate-release theophylline and aminophylline are interchangeable. Aminophylline (theophylline ethylenediamine) is 80% theophylline.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Respiratory Drug Therapy

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