David B. Church
Respiratory diseases in dogs and cats can be classified into respiratory problems brought about as a result of a specific abnormality of the respiratory system; so called primary respiratory disease, and bronchopulmonary problems which occur as a consequence of heart failure; so called secondary respiratory disease. This section will concentrate predominantly on considerations regarding the treatment of non-infectious aspects of primary respiratory diseases. This includes agents used to facilitate bronchodilation, to reduce coughing and various expectorants and mucolytics.
In order to understand the indications for, and action of, various drugs used in the treatment of respiratory disease an understanding of normal respiratory physiology is important and these considerations will be dealt with in the relevant sections.
Physiological bronchial tone is mediated by three neuroendocrine systems:
1. the parasympathetic system, the dominant efferent pathway in animals, which provides the baseline tone of mild bronchoconstriction that characterizes the normal respiratory tract
2. the sympathetic system which mediates these inherent bronchoconstrictive effects through beta 2-adrenergic-mediated bronchodilation and alpha 1-mediated bronchoconstriction as well as possibly beta 2-mediated reduction of parasympathetic bronchoconstriction
3. the non-adrenergic, non-cholinergic (NANC) system which apparently further mediates bronchodilation through various neurotransmitters such as vasoactive intestinal peptide.
Consequently bronchodilation may be achieved via anticholinergic agents (including beta 2 agonists), beta 2 adrenergic receptor agonists and agents such as the methylxanthines which produce bronchodilation at least in part due to increased intracellular cAMP levels in bronchial smooth muscle.
The use of bronchodilators in various disease states is based on the assumption that clinically significant bronchoconstriction exists. Although this has been shown in a small proportion of dogs with inflammatory bronchopulmonary disease, it is in cats where bronchoconstriction is a frequent feature of inflammatory bronchial disease. As the signs of bronchoconstriction can dominate the clinical syndrome, feline inflammatory airway disease is frequently referred to as "feline asthma" as it is thought to resemble the human syndrome of the same name.
It is worth noting that in the cat, as in man, "asthma" can no longer be thought of simply as reversible airway obstruction or "irritable airways". Current information suggests "asthma" should be viewed as an inflammatory disease that has bronchial hyperreactivity and bronchospasm as one of its consequences. Although some affected individuals will have an allergic basis to this inflammatory process others will not.
Asthmatic inflammation is initiated by the release of an enormous variety of inflammatory mediators, each having more than one effect on airway inflammation. The resultant vasodilation, and increased vasopermeability produces an influx into the bronchial tissues of inflammatory cells, which then release their own mediators with their own inflammatory effects. The chronic results are airway edema, smooth muscle hypertrophy, epithelial shedding and bronchial hyperreactivity to non-specific stimuli.
The complexity of this inflammatory process, driven by multiple mediators of inflammation with each mediator having numerous effects, would suggest that a drug affecting one mediator is unlikely to have substantial benefit, simply because there are so many mediators participating in the process. In addition, it seems likely that drugs which broadly address asthmatic inflammation are likely to be of more therapeutic benefit than agents that are basically modifiers of bronchoconstriction.
In man, recent clinical trials comparing the benefits of anti-inflammatory treatment with those of bronchodilator therapy in asthmatics have shown the usefulness of addressing the inflammatory process as the underlying problem, rather than attempting to correct some of the more dramatic clinical consequences of asthmatic inflammation.
Nevertheless symptomatic bronchodilator therapy remains a therapeutic option and certainly may have substantial benefit in some cases.
The following sections will concentrate on specific bronchodilators as well as the use of leukotriene-receptor antagonists, a group of drugs that can potentially modify a number of the mediators of asthmatic inflammation.
All adrenergic agonists have variable alpha and beta receptor affinity. In view of the distribution of alpha and beta receptors, non-selective beta receptor agonists such as isoprenaline or mixed alpha and beta receptor agonists such as adrenaline are more likely to produce cardiovascular side effects than similarly administered selective beta agonists. Consequently, drugs with preferential affinity for beta 2 receptors are likely to provide more effective bronchodilation with fewer side effects.
A possible exception may be with the treatment of acute allergic bronchospasm. In this situation, the M-2 receptor-mediated inhibition of cholinergic bronchospasm may be helpful. For this reason, the use of an adrenergic agent with both alpha 2 and beta 2 agonist activity may be beneficial in the peracute management of allergic bronchospasm. However, in view of the risks associated with administering systemic non-selective adrenergic agonists to a potentially hypoxic and already tachycardic patient, it is clearly preferable for them to be administered by inhalation rather than systemically.
Even when selective beta 2 agonists are used, the preferential activation of pulmonary beta 2 receptors may be enhanced by inhalation of small doses of the drug in aerosol form. This approach typically leads to rapid and effective pulmonary beta 2 receptor activation with low systemic drug concentrations.
Aerosol administration relies upon the delivery of drug distal airways which in turn depends on the size of the aerosol particles and various respiratory parameters such as tidal volume and inspiratory flow rate. Even in such a cooperative patient as man only approximately 10% of the inhaled dose enters the lungs. Effective aerosol therapy is possible for dogs and cats especially for short periods or in emergency situations. However the general inconvenience of long-term bronchodilator therapy raises significant compliance issues.
Although there are a large number of selective beta 2 receptor agonists commercially available for use in man, most are presented in various inhalant preparations which generally are unsuitable for regular use in small animals. The two principal beta 2 agonists currently marketed in preparations that can be readily and regularly used in small animals are terbutaline sulphate and albuterol sulphate.
Terbutaline is available as tablets, elixir and an injectable preparation suitable for subcutaneous use. The dose rate has been reported from as low as 0.1-0.2mg/kg/8h for the dog and cat given either orally or subcutaneously to as high as 1mg/kg/8h for an oral dose in the dog.
Albuterol is available as tablets and syrup as well as various inhalants. The dose rate in the dog is 0.02mg/kg/12h. This dose should be maintained for 5 days and if there has been no improvement nor any adverse effects the dose may be increased to 0.05mg/kg/8-12h. In animals that respond at this higher dose the dose should be reduced until the lowest effective dose has been determined for each patient.
Recent studies have confirmed albuterol and prednisolone act synergistically in producing bronchodilation in response to a standard bronchoconstricting stimulus. Consequently concurrent glucocorticoid therapy may be worth considering in patients proving refractory to albuterol's bronchodilatory effects. This may be given either as oral preparations or topically (see below).
Topical bronchodilator therapy can be achieved effectively in cats using a standard pediatric spacer equipped with a cat face mask on the 'patient' end. Most clinicians recommend using both a beta-blocker (such as albuterol) and topical glucocorticoids such as fluticasone. The dose of albuterol is two 'puffs' from a generic inhaler and is combined with a standard dose of inhaled fluticasone of 220ugm/puff. Both are vaporised in the spacer, the face mask placed over the cat's face and it is allowed to breath through the mask for a minimum of 7-10 seconds.
The inhalation procedure is usually given every 12 hours and is started in addition to oral prednisolone if the cat is symptomatic at the time. Usually the prednisolone can be stopped after 5-10 days and the inhalation continued for at least a further month. Assuming adequate control, the dose of fluticasone can then be reduced to 110µgm every 12 hours for another month and then stop. Whether or not the albuterol is required throughout this period is debatable. Some clinicians do not use albuterol except at times when cats are symptomatic.
The methylxanthines share several pharmacological actions of therapeutic interest. They relax smooth muscle, particularly bronchial smooth muscle, stimulate the central nervous system, are weakly positive chronotropes and inotropes as well as being mild diuretics. However it is as bronchodilators that they have been most widely used in small animal veterinary practice.
Caffeine, theophylline and theobromine are three naturally occurring methylated xanthines. All three are relatively insoluble and this solubility can be enhanced by the formation of complexes with a wide variety of compounds. The best known of these complexes is aminophylline which is the ethylenediamine complex of theophylline with differing quantities of water of hydration. 100mg of hydrous and anhydrous aminophylline respectively contains 79 and 86 mg of anhydrous theophylline. Conversely, 100mg of anhydrous theophylline is equivalent to 116mg of anhydrous aminophylline and 127mg of hydrous aminophylline. When dissolved in water, aminophylline readily dissociates to its parent compounds.
Because of theophylline's relatively low therapeutic index and pharmacokinetic characteristics, dose rates should be determined on lean body mass. Dose conversions between aminophylline and theophylline can be determined from the information present in the chemical structure section.
The dose rate of theophylline varies depending on the preparation used. In standard preparations the recommended dose rate in dogs is 10mg/kg/6-8h and cats 4mg/kg/8-12h. When using the sustained release preparations a dose of 20mg/kg/12h for dogs and 25mg/kg/24h for cats should be considered. (these doses recommendations are wrong--they are for products no longer available, not what is currently available in the US) Although there have been reports of varied bioavailability with different proprietary forms of sustained release preparations, Theo-Dur and Diffumal have both been shown to reliably have bioavailability greater than 95% in dogs.
The dose rate of aminophylline is 11mg/kg/8h in dogs and 5-6mg/kg/12h in cats.
The cough reflex is complex, involving the central and peripheral nervous system as well as the smooth muscle of the bronchial tree. It has been suggested that irritation of the bronchial mucosa causes bronchoconstriction, which in turn stimulates cough receptors located within the tracheo-bronchial tree. Afferent conduction from these receptors is via the vagus too possibly multiple centres within the medulla that are distinct from the actual respiratory centre. The drugs that can affect this complex mechanism are quite diverse. For example when coughing as a result of bronchoconstriction may be relieved by bronchodilators acting simply to dilate airways while other antitussive agents might act primarily on the peripheral or central nervous system components of the cough reflex. Generally however the most effective antitussives have been shown to elevate the threshold for coughing by poorly understood centrally mediated mechanisms.
Almost all respiratory tract disorders involving the large and small airways result in coughing. Frequently this can be viewed as a protective physiological process resulting in clearing of viscoid secretions produced by chronic airway inflammation. As prolonged contact between inflammatory mediators in the mucus and epithelial cells perpetuates inflammation any form of cough suppression needs to be instituted cautiously. However once clinical signs suggest the coughing is resolving, cough suppression may be desirable as chronic coughing tends to increase airway inflammation, increasing the risk of a vicious cycle of cough leading to mucosal irritation which creates further coughing. Additionally, chronic coughing for any reason will increase the risk of irreversible emphysema. Consequently cough-suppression may be particularly helpful in certain situations. Perhaps the most common condition where cough suppression plays an integral part in successful management is dynamic airway disease.
Typically drugs used to suppress coughing are categorized as opioid or non-opioid antitussive agents. Unfortunately, although most of the non-opioid antitussives are effective against coughing induced by various experimental techniques, the ability of these tests to predict clinical efficacy is limited. Consequently in different patients, therapeutic trials with various antitussives may be required in order to achieve effective cough suppression.
The principal non-opioid antitussive available to veterinarians is dextromethorphan. Dextromethorphan is generally marketed in "over the counter" formulations with various antihistamines, bronchodilators and mucolytics. A dose of approximately 2 mg/kg has been suggested although, as with most of the antitussive agents, higher doses are often required.
Antitussive effects may persist for up to 5 hours. In the author's experience, dextromethorphan's efficacy is significantly less than the various opioid antitussives. Its main advantage in most situations is its ease of availability and convenience.
Among other drugs which have been used as antitussives, the antihistamine diphenhydramine is perhaps the most ubiquitous. Its antitussive mechanism of action is unclear and controlled studies on its efficacy in dogs and cats are not available. As diphenhydramine may produce drowsiness in recommended doses its value as an antitussive in dogs and cats remains at best debatable.
The only oral opioid antitussives widely available are now codeine phosphate and hydrocodone.
Codeine has a high oral-parenteral potency for an opioid with oral administration of codeine providing around 60% of its parenteral efficacy. Once absorbed, codeine is metabolized by the liver with the largely inactive metabolites excreted predominantly in the urine. In man approximately 10% of administered codeine is demethylated to form morphine and both fee and conjugated forms of morphine can be found in the urine of patients receiving therapeutic doses of codeine. In man, codeine's plasma half-life is around 2 to 4 hours.
Codeine phosphate is contained in numerous "over the counter" analgesic preparations as well as in 30 and 60mg tablets which have restricted scheduling. The starting antitussive dose has been as low as 0.1-0.3mg/kg/8-12h and as high as 1-2mg/kg/6-12h. Whatever the starting point, the dose may need to be increased to achieve a satisfactory effect.
Hydrocodone is generally marketed in combination with homatropine as both an elixir and tablet formulations. The addition of homatropine is designed to enhance any reduction in respiratory secretions, which may come about as a result of the administration of hydrocodone. The dose rate in dogs is 0.22mg/kg/6-12h and the antitussive effect generally lasts between 612hours.
The viscosity of pulmonary mucus secretions depends on the concentrations of mucoproteins and deoxyribonucleic acid (DNA). While mucoprotein is the main determinant of viscosity in normal mucus, in purulent inflammation the mucoid concentration of DNA increases (due to increased cellular debris) and so does its contribution to mucoid viscosity.
In a proportion of patients with respiratory tract disease, significant bronchial inflammation will be associated with the presence of large amounts of relatively viscous, inflammatory exudate and mucus which is firmly attached to the lining of bronchioles and bronchii. By effectively increasing bronchial wall thickness, this thick adherent mucus can exacerbate the "lumen narrowing" effects of bronchial constriction; enhance the overall inflammatory process as well potentiating persistent coughing. In this situation mucolytic therapy may have some value in facilitating resolution of the inflammatory airway disease.
The two most frequently prescribed mucolytics in veterinary practice are bromhexine hydrochloride and acetylcysteine. It is also worth remembering that normal saline, directly administered to the airways by effective nebulisation therapy, is an extremely effective mucolytic and expectorant.
LEUKOTRIENE RECEPTOR ANTAGONISTS
Inflammation of the respiratory tract is frequently characterised by the classical markers of inflammation; accumulations of inflammatory cells and exudate. However, the specific structure and physiology of bronchi and bronchioles means that inflammation of these structures may also be associated with varying degrees of bronchoconstriction and, or, bronchospasm. Additionally "airway hyperreactivity" may become a standard response of sensitised patients to various inhaled compounds.
Although glucocorticoids remain the "gold standard" in controlling this inflammatory-induced bronchoconstriction, the leukotriene receptor antagonists represent a new class of drugs which may facilitate management of these various forms of bronchoconstriction.