BVSc (Hons) MMedVet (Med) PhD Dipl. ECVIM (Internal Medicine)
Bryanston Veterinary Hospital
PO Box 67092, Bryanston, 2021, South Africa
Part of a local mini-congress May 2009
Respiratory diseases in dogs and cats can be classified into primary (specific abnormality of the respiratory system) and secondary (consequence of heart failure). 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. Poly-pharmacy or multiple drug usage which gives minimal consideration to the actions of the drug, patient characteristics, the pathophysiology of the disease, or the possible consequence of the drug should be avoided.
In respiratory disease addressing one or more of the following is generally required:
- Disruption of mucous clearance
- Inflammation and pain
- Bacterial infections
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 broncho-pulmonary 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”. This disease should not be thought of simply as reversible airway obstruction or “irritable airways” but viewed as an inflammatory disease that has bronchial hyper-reactivity and bronchospasm as one of its consequences.
Bronchial tone is mediated by three neuro-endocrine systems:
- The parasympathetic system, which is the dominant efferent pathway, provides the baseline tone of mild bronchoconstriction that characterizes the normal respiratory tract.
- The sympathetic system mediates these inherent bronchoconstrictive effects through β2-adrenergic-mediated bronchodilation and α1-mediated bronchoconstriction as well as possibly α2-mediated reduction of parasympathetic bronchoconstriction.
- The non-adrenergic, non-cholinergic (NANC) system mediates bronchodilation through various neurotransmitters such as vasoactive intestinal peptide.
All adrenergic agonists have variable α and β receptor affinity. 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. The two ß2 agonists used in small animals are terbutaline and albuterol.
Terbutaline is a selective β2 receptor agonist which produces relaxation of smooth muscle found principally in bronchial, vascular and uterine tissues.
Albuterol is a selective β2 receptor agonist with pharmacological properties similar to terbutaline. The drug should be given for 5 days and if there has been no improvement or any adverse effects, the dose may be increased. In animals that respond at this higher dose the dose should be reduced until the lowest effective dose has been determined for each patient.
Albuterol and prednisolone act synergistically in producing bronchodilation in response to a standard bronchoconstriction stimulus. Thus concurrent glucocorticoid therapy may be worth considering in patients proving refractory to albuterol’s bronchodilatory effects.
The methylxanthines modulate respiratory function by being adenosine receptor antagonists, inhibitors of phosphodiesterase, interfere with calcium mobilization, and inhibit the release of histamine. The nett result is bronchodilation of both large and small airways, inhibition of mast cell degranulation, increased mucociliary clearance, and decreases the work associated with breathing. The most common drug used is aminophylline.
Anticholinergics compete with acetylcholine at muscarinic sites. In the respiratory tract they antagonise vagally mediated bronchoconstriction. Despite this, they are generally not clinically effective due to their non-selective interaction with different muscarinic receptors and their side effects.
The primary indication for use in small animals is for bronchodilation in acutely dyspnoeic animals and the treatment of choice for life-threatening respiratory distress induced by anticholinesterases.
DISRUPTION OF MUCOUS CLEARANCE
In respiratory disease mucous undergoes a physical change and becomes extremely viscous, affecting ciliary function. Effective mucous clearance stops resulting in an accumulation of mucous, which results in:
- Reduced airway diameter.
- Reduction in the penetration of antibiotics and the hosts defence mechanisms to the site of infection.
- Potentiates persistent coughing.
- Bacterial colonization.
- Reduced humidification of inspired air, trapping of foreign particles and the protection of mucoid surfaces from dehydration and injury from physical, chemical and infectious agents.
Treatment is aimed at optimising the muco-ciliary escalator by altering mucous production and its viscosity and enhancing the activity of ciliary action. Mucolytics are used to break down and decrease the viscosity of the mucous whereas expectorants promote an increase in the volume and a decreased viscosity of bronchial secretions. Ciliary activity can be improved through the use of ß-receptor agonists and methylxanthine derivatives.
Animals with lung disease are frequently dehydrated due to decreased water intake and increased fluid loss due to pyrexia and polypnoea, which contributes to increased mucus viscosity. Water and saline solutions can be used to liquefy hyperviscous mucous, which can be done by oral rehydration, parenteral fluids, and via inhalation of water vapour (steam) or saline aerosols (nebulisation).
The viscosity of pulmonary mucus secretions depends on the concentrations of mucoproteins and presence of DNA. While mucoprotein is the main determinant of viscosity in normal mucus, in purulent inflammation the concentration of DNA increases due to increased cellular debris, which contributes to mucoid viscosity. Mucolytic drugs break down the disulfide bonds of mucoproteins resulting in a decrease in viscosity.
Acetylcysteine reduces viscosity of both purulent and non-purulent secretions as 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. Acetylcysteine can be given by aerosol or orally, however, administration by aerosol may cause bronchospasm, ciliary inhibition and severe coughing.
Bromohexine increases mucus viscosity by increasing lysosomal activity. This increased lysosomal activity enhances hydrolysis of acid mucopolysaccharide polymers, which significantly contributes to normal mucus viscosity. In purulent bronchial inflammation, bronchial mucus viscosity is more dependent upon the large amount of DNA fibres present. As bromohexine does not affect these DNA fibres, its mucolytic action is limited in these situations. At high doses it can act as an antitussive and will increase the concentration in the bronchial mucous of tetracyclines, sulphonamides and erythromycin.
Decongestants reduce the production and accumulation of inflammatory oedema in the nasal passages but are a seldom used in veterinary practice. Drugs are applied topically and include adrenalin and phenylephrine. Rebound phenomenon often occurs, which as the as the effect of the drug wears off the condition returns, often worse than before.
Expectorants promote the removal of secretions from the respiratory tree by increasing the volume and reducing the viscosity of respiratory secretions but as a whole only make a slight contribution to therapeutic success. Steam, volatile oils, and iodine preparations can all act as expectorants.
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 to possibly multiple centres within the medulla that are distinct from the actual respiratory centre.
Almost all respiratory tract disorders involving the large and small airways result in coughing. 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.
Another important aspect is to differentiate between a productive cough and non-productive cough. A productive cough is a protective reflex that removes secretions from the lungs, which might otherwise become congested with plugs of mucous providing sites for infection and disturbance of effective gas exchange. This type of cough should not be abolished and may be encouraged by expectorants. A non-productive cough particularly if it is chronic and continuous may in itself cause chronic respiratory parenchymal changes such as emphysema and fibrosis. It is also distressing and exhausting to the animal and may irritate the owner. Such a cough may be treated with cough suppressants.
Coughing can be treated by:
- Removing the irritant through the use of mucolytics and expectorants.
- Blocking peripheral receptors to induce bronchodilation.
- Blocking the cough centre in the medulla.
Typically drugs used to suppress coughing are categorized as opioid or non-opioid antitussive agents.
Dextromethorphan is a synthetic cough suppressant that acts centrally to elevate the cough threshold but does not have addictive, analgesic or sedative action. At normal doses it does not produce respiratory depression or inhibit ciliary activity. Its antitussive effects may persist for up to 5 hours.
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. Often the dose may need to be increased to achieve a satisfactory effect.
Hydrocodone exhibits the same properties of other opiate agonists but has increased antitussive properties compared to codeine. The mechanism of this effect seems to be direct suppression of the cough centre within the medulla. Hydrocodone may also reduce respiratory mucosal secretions through undetermined mechanisms. In dogs the antitussive effect generally lasts between 6-12 hours.
Dihydrocodeine also acts centrally to raise the cough threshold. It is marketed as an elixir, which is relatively palatable and well absorbed.
Butorphanol is an effective antitussive as well as analgesic. In dogs it has been shown to elevate CNS respiratory centre threshold to CO2 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.
Diphenoxylate is an opioid agonist traditionally used as an anti-diarrhoeal agent. However it also has effective antitussive activity, presumably through direct suppression of the cough centre.
INFLAMMATION AND PAIN
In most respiratory diseases arachidonic acid is released from reactive cells in tissue inflammation and is converted into a number of derivatives of which the prostaglandins and leukotrienes are powerful endogenous bronchoconstrictors.
Glucocorticoids induce the formation of lipocortins in cells containing glucocorticoid receptors. These lipocortins then inhibit phospholipase A2 which is responsible for the mobilization of arachidonic acid from membrane lipids. Corticosteroids are therefore effective in preventing the bronchoconstriction often associated with inflammatory conditions.
Indications for the use of corticosteroids include rhinitis, laryngitis, bronchitis and allergic lung disease. Inhaled steroids are the standard of care to treat humans with asthma and can be used with equal success rate as oral prednisolone in the treatment of dogs and cats with respiratory diseases using a spacer (paediatric aero-chamber or an Equi-haler®).
Histamine released due to inflammation or hypersensitivity reactions results in contraction of bronchial smooth muscle via H1-receptors in dogs. However in cats, relaxation of respiratory smooth muscle results due to stimulation of both H1- and H2-receptors. Antihistamines will counter the bronchoconstriction and will often help in cough control in dogs.
Diphenhydramine reduces the bronchoconstriction, production of secretions, and respiratory irritation due to its local anaesthetic effect and it has a strong sedative effect.
Non steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs inhibit the metabolism of arachidonic acid at one or more steps limiting the production of the inflammatory mediators, prostaglandins and thromboxane. They have a limiting effect on inflammation and have potent analgesic and antipyretic effects. However, by inhibiting the COX enzyme system shunting towards the LOX pathway occurs, which promotes the formation of leukotrienes which are potent bronchoconstrictors.
Bacterial infections of the respiratory system are a common occurrence in the dog, but less so in the cat. They often occur as a result of the pulmonary defence mechanisms being compromised, such aspiration of foreign material, chronic bronchial disease, foreign bodies or viral diseases.
In dogs organisms that most commonly cause pneumonia include: Pasteurella multocida, Streptococcus spp., Staphylococcus spp, Pseudomonas, Escherichia coli, Klebsiella spp, and Bordetella bronchiseptica.
Ideally the selection of antibiotics should be based on bacterial culture and sensitivity testing, however, empirical or initial antibiotic selection can be based on the examination of a tracheal wash. The identification of cocci usually indicates a streptococci or staphylococci which are gram positive and often susceptible to amoxicillin, potentiated sulphonamides, and cephalosporins. Bacterial rods are almost always gram-negative bacteria and suitable antibiotics include potentiated sulphonamides, gentamicin, amikacin, and fluoroquinolones. In cases were the bacteria are not identified, antibiotics should be selected to cover both gram-negative and gram-positive such as penicillin with gentamicin and potentiated penicillins (amoxicillin with clavulanic acid).
Concentrations of antibiotics within the pulmonary parenchyma tend to correlate well with serum concentrations. Some antibiotics, e.g. the fluoroquinolones, will result in concentrations in the lungs that are 4-5 times higher than in the serum. In most infections the routine administration of appropriate antibiotics is adequate to achieve a therapeutic response. However, in severe cases, antibiotics should be administered intravenously for the first 3-7 days. Therapy should be administered for 4-8 weeks, ideally 1-2 weeks after resolution of the condition.
In cardiogenic oedema therapy is aimed at decreasing of pulmonary blood pressure, which can be achieved by either causing diuresis or by promoting the pooling of blood. Furosamide is the drug of choice as it promotes both diuresis and the pooling of blood. The latter mechanism has been linked to the drugs’ ability to induce dilation of the pulmonary vasculature.
Although a large number of drugs have been tried in the treatment of these animals, pharmacological treatment generally appears to be ineffective.