Respiratory Therapeutics: Are the Choices Limited?
World Small Animal Veterinary Association World Congress Proceedings, 2015
Brendan Corcoran1, MVB, DipPharm, PhD, MRCVS
1Professor, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Scotland, UK

There are a variety of mechanisms that can be modified pharmacologically to improve respiratory function and counter respiratory disease, but also a clear understanding of how the respiratory system protects itself and functions in the face of disease is clinically worthwhile.

Respiratory Defence Mechanisms

The nasal cavity turbinates provide the surface area required for warming and humidifying inspired air and the mucosa traps and filters particulate material. The mucociliary apparatus allows cranial clearance and is augmented by mucus secreted by goblet cells and ciliary function. First major defence mechanisms are sneezing, cough and laryngospasm reflexes. For the lower airways smooth muscle contraction, goblet cell production of mucus, the mucociliary apparatus and the cough reflex all act to protect the lung. At the respiratory bronchiole and alveolar level the main protective mechanisms include rostral movement of material using capillary action, followed by cough, and trans-epithelial transport using the alveolar macrophage system. The latter can also involve polymorphonuclear leucocytes (typically neutrophils). Material entering the alveolar interstitium is either sequestrated at that site or carried away via lymphatics.

Regulation of Bronchial Smooth Muscle Tone

This is mediated via reciprocal relationship between cAMP and cGMP. Increased levels of one of these second messengers are associated with decreased levels of the other and increased cAMP promotes relaxation whereas increased cGMP promotes bronchoconstriction. cAMP is increased by β2-adrenoreceptor stimulation, H2 receptor stimulation and decreased levels of phosphodiesterases, and decreased by α-adrenergic stimulation. cGMP increases with β2-receptor stimulation (i.e., by circulating adrenaline) via adenyl cyclase (AC) activation, histaminergic (H2) receptor stimulation and decreased levels of phosphodiesterases and is increased by muscarinic (M3) receptor stimulation (i.e., by Ach from vagus) and by histaminergic (H1) stimulation.

Respiratory Disorders

In the normal lung the interaction between sensory receptors and mediators of bronchial tone is balanced. Disruption of such balance results in bronchospasm, bronchoconstriction, inflammation, increased mucus secretion and changes in mucus viscoelasticity. This may lead to bronchial wall oedema, mucus accumulation and airway obstruction. Chronic cases progress toward fibrosis and emphysema.

Bronchodilators

Temporary abnormal contraction of the smooth muscle of the bronchi that results in an acute narrowing and obstruction of the respiratory airway is characteristic of asthma and respiratory infection, but is unlikely in chronic lung diseases. The main purpose of treatment is to induce smooth muscle relaxation using bronchodilators which include β-adrenoreceptor agonists, methylxanthines and cholinergic antagonists (anticholinergic drugs are rarely used in dogs and cats). β2-agonists relax airway smooth muscle and are the most effective bronchodilators. β2-receptors also stimulate airways mucus secretion. Specifics β2-agonists include (only a few of these have been used in animals) short acting agents such as Salbutamol (VentolinTM) terbutaline (BricanylTM) and clenbuterol (VentipulminTM). Maximum effects occur within minutes and are therefore the preferred drugs to treat severe acute asthma. Duration of action is 4–6 h.

Salbutamol and terbutaline have been used in small animals. Clenbuterol (VentipulminTM) is a licensed veterinary drug and used in horses with little value in small animals. Longer acting agents include salmeterol which is administered by inhalation with a duration of action of 12 h.

Unwanted side effects can include refractoriness with chronic use, more viscid mucus and interfering with cilia movement and hypokalemia, tremors, nausea, vomiting, tachycardia.

The methylxanthines act by reducing cAMP breakdown via PDE inhibition. Advantages over other bronchodilators include increased respiratory muscle strength, decreasing effort associated with breathing, which may be important in animals with chronic pulmonary disease, but this can be at the expense of increased oxygen consumption (including CNS stimulation). This class includes caffeine, theobromine, theophylline, and the salt preparations include aminophylline and etamiphylline (Corvental-DTM & Millophylline-VTM). There is a high risk of side effects with overdosage such as tachycardia, agitation, cardiac arrhythmias, hypotension, seizures and even death, and their overall effects on bronchomotor tone has been questioned.

Antiinflammatory Therapy

This mainly involves use of glucocorticosteroids, but there is some interest in the use of NSAIDs. Glucocorticosteroids reduce airway inflammation and decrease pulmonary eosinophil infiltration, which make them the preferred drugs to treat asthma and respiratory disease where eosinophil infiltration predominates. They also enhance bronchodilation via β2 up regulation. Dexamethasone is the most effective against eosinophils and can be followed by oral prednisolone aiming for alternate day low dosing and eventual withdrawal. Delivery of glucocorticosteroids by inhalation (with or without an added bronchodilator) can overcome the problem of systemic effects and appears particularly useful in cats. Fluticasone with salmeterol (Seretide®) is commonly used in dogs and cats for inhalation therapy.

NSAIDs are often used to assist with controlling airway and lung inflammation, but the problem of blocking protective eicosanoid pathways is a consideration. Often they have value in controlling pyrexia in pneumonia cases treatment in combination with antibacterial therapy. Flunixin, ketoprofen and carprofen have been used successfully as adjuncts to the antibacterial treatment of bovine respiratory disease, but whether the same benefits can occur in cats and dogs is unknown.

Mucolytics

Under steady state conditions mucus confers protection against shear stress and chemical damage to the respiratory system. Mucus production, secretion rate and properties are severely affected in chronic inflammatory conditions and this leads to decreased capacity of the lungs and increased respiratory work. Mucolytics breaks down thick, dry mucus. They may act on mucus secreting cells or on mucus directly. Modifiers of mucus synthesis include Bromhexine (BisolvonTM) and dembrexine (SputolosinTM) and are often used to treat chronic bronchitis. They reduce the viscosity of secreted mucus possibly by increasing lysosomal breakdown of mucopolysaccharide (MPS) within the gland cell. True mucolytics include acetylcysteine and work by reducing viscosity by breaking or blocking formation of disulphide bridges, are often administered as an aerosol limiting their penetration into the distal airways. Their efficacy in companion animal respiratory disease is unproven, but they are usually tried in chronic bronchitis cases, and discontinued if there is no appreciable benefit.

Antitussives

Antitussives can act centrally (depressing the cough centre in the brain) or peripherally (depressing cough receptors in the airways). Only the centrally acting drugs are of certain use in veterinary patients and include narcotic opiate analgesics (codeine, hydrocodone, butorphanol) and non-narcotic opioids (dextromethorphan, diphenoxylate). Their use is limited to those cases where coughing is of little value, and cannot be controlled by other means, or is causing significant discomfort to the dog. Care should be exercised in their use when coughing is of benefit to the patient as in chronic bronchitis and pneumonia. Tolerance can develop to the opiate drugs and can be overcome by intermittent use.

Antibacterial Drugs

The over-use of antibiotics in veterinary and human medicine has become an issue of concern and veterinarians should consider their role in responsible use of these important drugs. Typically bacteria found in respiratory disease reflect over-growth of the normal commensal population and are, therefore, usually gram-negative aerobes. An antibiotic can be selected on that empirical basis and is likely to be effective (e.g., fluoroquinolones), but concurrent infection with gram-positive organisms and anaerobes must be considered in severe pneumonia and so a combination of antibiotics are often needed to effect a cure. Selection on the basis of culture and sensitivity is the ideal, but not readily achievable considering the difficulty in obtaining samples and the delay in obtaining results in severely affected cases. The recent introduction of pradofloxacin which has enhanced anti-gram-positive activity might be a single drug approach to dealing with severe bacterial bronchopneumonia. More traditionally a typical selection might be any three of clindamycin, a cephalosporin, potentiated sulphonamides and an early generation fluoroquinolone. Clavulanate-potentiated amoxicillin (e.g., Augmentin) is often used in general practice and can be effective for simple infections, but is rarely efficacious in severe pneumonia cases. This is in part due to limitation on its penetration into infected lung. However, it might be considered to be used intravenously in severe infections prior to oral administration of a selected β-lactam (penicillin or cephalosporin). An alternative IV approach is to use cefuroxime. Where Mycoplasma is suspected then doxycycline is the antibiotic of choice.

In the severely compromised patient IV administration of antibiotics needs to be considered and delivered by inhalation if possible for nephrotoxic antibiotics such as gentamycin. Gentamycin can also be considered for highly resistant Pseudomonas infection, but parenteral fluoroquinolones or ticarcillin are more feasible options.

In severe bronchopneumonia treatment should be for a minimum of 4 weeks, with cessation of therapy only if there has been complete resolution of clinical signs and radiographic evidence suggesting a cure. Otherwise, therapy should be extended for a further 4 weeks; providing the first four weeks did give significant improvement. In the case of a partially responsive chronic lobar pneumonia, lung lobectomy is the best approach rather than chronic antibacterial therapy. In cases where recurrent infection is a problem, such as with chronic bronchitis, intermittent course of antibiotics will be needed to avoid catastrophic pneumonia developing.

References

Responsible antibiotic usage:

1.  www.bsava.com/Resources/PROTECT.aspx.

2.  www.fecava.org/sites/default/files/files/2014_12_fecava_responsible%20use%20AM.pdf.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Brendan Corcoran, MVB, DipPharm, PhD, MRCVS
Royal (Dick) School of Veterinary Studies
The University of Edinburgh
Roslin, Scotland, UK


MAIN : Internal Medicine : Respiratory Therapeutics
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