Professor, Department of Veterinary Clinical Science, The Royal Veterinary College
North Mymms, Hatfield, Hertfordshire, UK
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 β2-adrenergic-mediated bronchodilation and α1-mediated bronchoconstriction as well as possibly α2-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.
The mechanisms involved in cholinergic bronchoconstriction are complex and incompletely understood. Intracellular effects depend in part on modifications of intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The effects of these two secondary messengers are reciprocal; hence increased concentrations of one are associated with decreased concentrations of the other. Cyclic AMP is increased by β2-receptor stimulation and decreased by activation of α1-adrenergic receptors. In contrast a variety of different inflammatory mediators, activation of H1 receptors, increased intracellular Ca concentrations and muscarinic effects of acetylcholine increase cGMP levels.
Acetylcholine's actions are mediated via a number of mechanisms which are not all cAMP or gAMP-dependent. These include increasing intracellular concentrations of inositol 1,4,5-triphosphate (ITP) and diacylglycerol (DAG) as well as promoting Ca influx through L-type Ca channels. The ITP effects are thought to be responsible for the initial phase of bronchial smooth muscle contraction, mediated via a transient increase in intracellular calcium concentration through release from the sarcoplasmic reticulum. Despite this apparent cAMP-independence, it has been postulated that it may be a cholinergic mediated decrease in cAMP which is the cause of the increased intracellular ITP concentration.
Although this first phase may be AMP-independent, both ITP and DAG levels appear to be involved in the maintenance of contraction via modification of cAMP levels through unknown mechanisms.
As mentioned above adrenergic stimulation can result in both α1-adrenoreceptor mediated bronchial constriction, α2-adrenoreceptor mediated bronchodilation probably through inhibition of cholinergic bronchoconstriction or bronchodilation through activation of β2 adrenoreceptors. The bronchodilatory effects of β2 adrenoreceptors are mediated not only through increasing cAMP concentrations but also perhaps more importantly through a cAMP-independent pathway that involves activation of a large-conductance calcium-activated potassium channel. Activating this channel allows an extracellular potassium efflux, increase in trans-membrane potential and hence a reduction in Ca influx through the voltage-dependent L-type Ca channels, thereby resulting in bronchodilation.
Consequently bronchodilation may be achieved via anticholinergic agents (including α2agonists), β2 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 α and β receptor affinity. In view of the distribution of α and β receptors, non-selective β receptor agonists such as isoprenaline or mixed α and β receptor agonists such as adrenaline are more likely to produce cardiovascular side effects than similarly administered selective β agonists. Consequently, drugs with preferential affinity for β2 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 α2receptor-mediated inhibition of cholinergic bronchospasm may be helpful. For this reason, the use of an adrenergic agent with both β2 and α2 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 β2 agonists are used, the preferential activation of pulmonary β2 receptors may be enhanced by inhalation of small doses of the drug in aerosol form. This approach typically leads to rapid and effective pulmonary β2 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 β2 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 ß2 agonists currently marketed in preparations that can be readily and regularly used in small animals are terbutaline sulphate and albuterol sulphate.
Terbutaline sulphate: Terbutaline is a selective β2 receptor agonist which produces relaxation of smooth muscle found principally in bronchial, vascular and uterine tissues. 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 sulphate: Albuterol is a selective β2 receptor agonist with pharmacological properties similar to terbutaline. 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 0.5mg/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 B-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. 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 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 110mgm every 12 hoursfor 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.
Theophylline and aminophylline: 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.
The pharmacokinetics of theophylline has been extensively studied in a number of species. After oral administration rate of absorption is limited principally by dissolution of the dosage form in the gut. Bioavailability in both cats and dogs is generally 100% when non-sustained release preparations are used. However sustained release preparations may have a more variable bioavailability. One study in dogs suggested four different sustained release preparations has bioavailabilities varying from 30-76% however other investigators found bioavailability to be greater than 95% in studies using two of these four products.
Theophylline is only weakly protein bound (7-14%) with a relatively low volume of distribution (0.82 L/kg, dogs; 0.46 L/kg, cats). Because of this low volume of distribution and theophylline's poor lipid solubility, it is recommended that obese animals be dosed on a lean body mass basis.
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. Although there have been reports of varied bioavailability with different proprietary forms of sustained release preparations, Theo-Durr 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.
Dextromethorphan hydrobromide: Dextromethorphan hydrobromide is a synthetic cough suppressant which acts centrally to elevate the cough threshold. It does not have addictive, analgesic or sedative action and in usual doses does not produce respiratory depression nor inhibit ciliary activity. Dextromethorphan binds to central binding sites that appear to be distinct from standard opioid receptors. The non-opioid nature of these sites is reinforced by the inability of naloxone to reverse dextromethorphan's effects.
Dextromethorphan is generally marketed in "over the counter" formulations usually syrups or lozenges) combined 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.
Diphenhydramine: 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.
Codeine phosphate. Due to reduced first-pass hepatic metabolism 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 tartrate: Hydrocodone exhibits the properties of other opiate agonists however has reportedly increased antitussive properties compared to codeine. The mechanism of this effect seems to be direct suppression of the cough centre within the medulla. It has been suggested that hydrocodone may also reduce respiratory mucosal secretions through undetermined mechanisms.
In dogs the antitussive effect generally lasts between 6-12 hours.
The dose rate in dogs is 0.25mg/kg/6-12h. Hydrocodone is only 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.
Dihydrocodeine tartrate: Hydrocodeine also acts centrally to raise the cough threshold. Its other CNS activities seem to be markedly less than codeine. Dihydrocodeine is marketed as an elixir, which is relatively palatable and well absorbed. A starting dose rate of 2mg/kg/8-12h is recommended although higher doses may be required for satisfactory therapeutic effect.
Butorphanol: Butorphanol is an effective antitussive as well as analgesic. In dogs it has been shown to elevate CNS respiratory centre threshold to pCO2 but unlike other opioid agonists it does not suppress respiratory centre sensitivity. Butorphanol is well absorbed orally however a significant first-pass effect results in less than 20% appearing in the systemic circulation. It is well distributed and in man approximately 80% protein bound.
The antitussive dose of butorphanol in dogs is 0.55-1.1mg/kg/6-12h orally or 0.055-0.11mg/kg/6-12h subcutaneously.
Diphenoxylate: General pharmacokinetics and pharmacodynamics: Diphenoxylate is an opioid agonist traditionally thought of exclusively as an antidiarrheal agent. However it also has effective antitussive activity, presumably through direct suppression of the cough center. In most countries it is only available in combination with atropine as an anti-diarrheal agent. In dogs, diphenoxylate can be used in this combination as an effective antitussive with minimal side effects. The dose rate is approximately 0.25mg/kg8-12h orally.
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 described below. In man, guaifenesin has been proposed as an oral expectorant or mucolytic. However, evidence for its efficacy in this role is lacking in animals and currently its use in veterinary practice is confined to its significant muscle relaxant activity. It is also worth remembering that normal saline, directly administered to the airways by effective nebulisation therapy, is an extremely effective mucolytic and expectorant.
Bromhexine increases mucus viscosity by increasing lysosomal activity. This increased lysosomal activity enhances hydrolysis of acid mucopolysaccharide polymers, which significantly contribute to normal mucus viscosity. It should be remembered that in purulent bronchial inflammation, bronchial mucus viscosity is more dependent upon the large amount of DNA fibres present. As bromhexine does not effect these DNA fibres, its mucolytic action is limited in these situations.
It has also been suggested that bromhexine increases the permeability of the alveolar/capillary barrier resulting in increased concentrations of certain antibiotics in luminal secretions. Furthermore over time (2-3days) bromhexine results in a significant increase in γ-globulin concentrations and a decline in albumin and γ-globulin concentrations in respiratory secretions. The increased g-globulins are IgA and IgG while IgM levels remain unchanged. It has been hypothesized that because of these effects concurrent administration of bromhexine and an antimicrobial agent will facilitate treatment of infectious tracheobronchitis.
The mucolytic dose of bromhexine hydrochloride in dogs and cats is 2mg/kg/12h orally for 7 to 10 days then 1mg/kg/12h for a further 7-10 days.
When administered directly into airways, acetylcysteine reduces viscosity of both purulent and nonpurulent secretions. This effect is thought to be a result of the free sulphydryl group on acetylcysteine reducing the disulphide linkages in mucoproteins which are thought to be at least partly responsible for the particularly viscoid nature of respiratory mucus. The mucolytic activity of acetylcysteine is unaltered by the presence of DNA and increase with increasing pH.
For effective mucolytic activity, an acetylcysteine solution should be nebulised and administered directly to the respiratory mucosa as an aerosol. The dose rate in dogs and cats is 50ml/kg for 30 minutes every 12 hours.
Acetylcysteine is available as 10% and 20% solutions of the sodium salt in various sized vials. This solution can be readily used in a nebuliser undiluted although dilution with sterile saline will reduce the risk of reactive bronchospasm.