I. INTRODUCTION

The primary function of the respiratory system is gas exchange between the inspired air and the pulmonary artery blood. Because of the large surface area of the alveoli and exposure to the environment, this organ system is prone to antigen–allergy responses and infection. The defenses of the respiratory system include hypersecretion of mucus, sneezing and coughing reflexes, bronchoconstriction, and macrophage activation and inflammation. Pharmacology of the respiratory system centers around these defense mechanisms and can be simplified into seven categories: (1) elimination of excess secretions and membrane congestion, (2) bronchiole dilation when excessive constriction has occurred, (3) cough suppression when it is nonproductive and detrimental to the animal, (4) control of infection and inflammation, (5) decrease pulmonary hypertension, (6) stimulate the peripheral chemoreceptors and the central respiratory center, and (7) exogenous surfactant.

II. SECRETIONS.

A thin layer of mucus coats the surface of all airways from the bronchioles to the larynx. This mucus is secreted by Clara cells, goblet cells, and submucosal bronchial glands located within the respiratory epithelium. Mucus protects airways by entrapping inhaled particles, humidifying inspired air, and maintaining mucosal hydration. Cilia, on the apical surface of respiratory epithelial cells, propel mucus out of smaller airways into the trachea and up to the larynx to be swallowed or expectorated. The mucociliary escalator is essential for the removal of airway secretions, pathogens, cellular debris, and inhaled particulate matter from the respiratory tract. Mucoprotein content of the mucus and transepithelial movement of water and ions determine the viscosity of normal mucus. Thick mucus can also be due to the presence of bacterial and neutrophil cellular debris. The cough reflex is very important for clearance of viscous mucus. Too much mucus narrows the lumen of bronchi restricting airflow and stimulates coughing. If coughing does not rid the airway of mucus, there are several pharmacologic options in addition to treating the underlying respiratory disease.

A. Increasing or facilitating the removal of excess, accumulated secretions. By decreasing the viscosity of these bronchial secretions, the normal action of the cilia and reflex coughing may be more effective.

1. Methods designed to loosen secretions by hydration of the mucus.

a. Nebulizer (aerosol) therapy with sterile or bacteriostatic water or saline produces a liquid particle suspension within a carrier gas (room air or oxygen) which, when inhaled, will add water to the airway mucus layer.

b. Always use physiotherapy in conjunction with nebulization.

(1) Improve tidal ventilation by mild-forced exercise after nebulization.

(2) Manually stimulating a cough reflex via chest wall coupage, vibration, or tracheal manipulation.

c. Efficacy is debatable.

d. Small volume jet or ultrasonic nebulizers produce particles of 0.5–3 microns, which are best for deposition in the lower respiratory tract.

e. Large volume aerosol therapy may be beneficial in lobar pneumonia. Done with a bland aerosol (sterile saline) in an enclosed cage with a large ultrasonic nebulizer for 30–45 minutes 2–4 times per day.

2. N-Acetylcysteine (N-acetyl-l-cysteine) is a derivative of l-cysteine and acts as a mucolytic drug.

a. N-Acetylcysteine (NAC) breaks the disulfide bonds within the mucus molecules and decreases the viscosity.

b. NAC will not only alter the viscosity of normal mucus but also the thick mucus that results from the addition of bacterial and neutrophil cellular debris.

c. This drug is usually aerosolized and inhaled by the patient, but a powder form is available and can be formulated for oral use.

d. Proven benefits from NAC have not been demonstrated in veterinary patients and aerosolized, it may cause airway irritation and bronchoconstriction.

3. Bromhexine HCl is a frequently prescribed mucolytic.

a. Enhances the hydrolysis of acid mucopolysaccharides that significantly contributes to mucus viscosity.

b. Does not alter protein in the mucus, which originates from bacteria or neutrophil cellular debris.

c. May increase the concentration of certain antibiotics in the alveoli by altering the permeability of the alveolar/capillary membranes.

B. Expectorants theoretically make the bronchiole secretions less viscous but their efficacy is questionable.

1. Potassium iodide is an oral saline expectorant, which causes irritation to the gastric mucosa that in turn increases bronchiole secretion through a vagal reflex.

2. Guaifenesin is a guaiacol (wood tar) derivative that acts as an expectorant and increases airway particle clearance in humans.

a. Guaifenesin may stimulate the gastric mucosa and increase respiratory tract secretions via reflex.

b. The volume and viscosity of secretions does not appear to change.

c. This compound is primarily found in over-the-counter human cough preparations.

C. Decongestants shrink the nasal mucosa and allow air to pass more freely. Sinusitis or reverse sneezing are other indications for decongestants.

1. H₁-antihistamines are commonly used for allergic-induced symptoms and chronic rhinitis in people but efficacy in animals is not documented. (See Chapter 3 for the pharmacology of H₁-antihistamines.)

a. Diphenhydramine

b. Dimenhydrinate

c. Chlorpheniramine

d. Hydroxyzine

2. Sympathomimetic drugs (α-receptor agonists) may be given orally or topically as nasal sprays to avoid their systemic effects. However, nasal sprays are not well tolerated in animals. Their primary effect is to constrict the precapillary arterioles, reduce blood flow, and reduce the extracellular fluid in the nasal mucosa. Nasal discharge consequently will be reduced and resistance to airflow through the nasal cavity will decrease. (See Chapter 2 for information on the pharmacology of sympathomimetics.)

a. Ephedrine

b. Pseudoephedrine

c. Phenylephrine. This drug has been used to relieve anesthesia (recumbency)-induced nasal congestion and edema in horses. About 30 minutes before anesthetic recovery and removal of the endotracheal tube, phenylephrine is sprayed or squirted into the ventral meatus of each nostril with the external nares elevated.

III. CONTROL OF INFECTION AND INFLAMMATION.

Antibiotic choice should ideally be based on culture and sensitivity or cytology with a Gram’s stain.

A. Antibacterial drugs that have a good spectrum of activity. (See Chapter 15 for information on the pharmacology of antibacterial drugs.)

1. Upper airway disease—Gram-positive spectrum is best.

2. Lower airway disease—Gram-negative spectrum is best.

a. Cephalosporins

b. Potentiated sulfonamides

c. Amoxicillin

d. Amoxicillin/clavulanate

e. Fluoroquinolones

3. Aerosolized antibiotics may be helpful in selected cases of infectious tracheobronchitis.

B. Glucocorticoids

1. Corticosteroids are important for the treatment of antigen-induced inflammatory bronchial disease such as chronic obstructive pulmonary disease (heaves) in horses and feline bronchial disease (asthma), as well as chronic bronchitis in dogs. Glucocorticoids reduce mucus hypersecretion, bronchial mucosal thickening, and airway smooth muscle constriction. (See Chapter 12 for more information on glucocorticoids.)

a. Oral intermediate-acting steroids are preferred for ease of dosage adjustments.

(1) Prednisolone

(2) Prednisone

b. Fluticasone is an inhaled glucocorticoid that is being used more frequently in animals.

(1) It is available in a multidose inhaler (MDI) for human inhalation.

(2) An animal mask and spacer are needed for administration.

(3) It has 18× the affinity of dexamethasone for human glucocorticoid receptors.

(4) Only 30% of the administered dose reaches the airways of the lung.

(5) It may take 1–2 weeks of administration to see the maximum effects.

c. For other inhaled glucocorticoid aerosol drugs see Table 10-1.

C. Leukotriene receptor antagonists are a new type of therapy. Leukotrienes are potent bronchoconstrictors and trigger inflammatory responses such as edema formation.

1. These modulators of inflammation can be used instead of corticosteroids.

2. Drugs that antagonize leukotriene receptors are zafirlukast, zileuton, and montelukast.

3. Zafirlukast has been tested in cats with experimental asthma and found not to be beneficial.

4. Whether these drugs are of any use in respiratory therapy is yet to be determined.

D. Nonsteroidal anti-inflammatory drugs are seldom used to treat inflammatory respiratory diseases because they tend to inhibit cyclooxygenase more than lipooxygenase enzymes. Aspirin has been used in the treatment of thromboembolism in cases of heartworm disease.

E. Serotonin receptor inhibition may be beneficial for feline “asthma.” Cyproheptadine is the only drug in this category currently thought to be beneficial. (See Chapter 3 for information on cyproheptadine.)

F. Cyclosporine is an immunosuppressant drug but has been shown to be beneficial in experimental models of feline bronchial disease “asthma.”

G. Mast cell stabilizers are used in human medicine to treat allergic asthma. These cromones, cromoglycate and nedocromil, prevent the release of inflammatory mediators from mast cells by inhibiting the influx of calcium. They are administered by inhalation and efficacy in animals is not documented. (See Chapter 3 for information on cromolyn sodium.)

TABLE 10-1. Drugs Available as Metered Dose Inhalers (MDI)

IV. COUGH SUPPRESSION

Cough Suppression and normalization of other respiratory reflexes. Sneezing and reverse sneezing, coughing, and airway narrowing reflexes that result in laryngospasm and bronchospasm are reflexes that are part of the normal pulmonary defenses and should not be suppressed unless they are excessive or debilitating.

A. Coughing is the sudden and loud ejection of air from the lungs. It is a normal protective reflex that is necessary in the diseased animal. The sensory receptors for the reflex cough are subepithelial irritant or stretch receptors that are numerous in large airways and innervated by the vagus nerve. Foreign bodies or excessive amounts of mucus on the surface of the airways can mechanically deform a sensory receptor and stimulate the cough reflex. Inflammation of the airway, for example, a viral infection, may result in the receptors becoming hyperresponsive. During a cough, the intrapleural pressure rises dramatically against a closed glottis and as a result the intrathoracic airways are compressed. Air is expelled with considerable noise through a narrowed airway and material is dislodged from the walls of large airways. Coughing is usually a good way for the animal to clear mucus from large bronchi and the trachea, but not from the smaller distal bronchi and bronchioles. Coughing is frequently a beneficial reflex and should not be suppressed unless it is dry (nonproduction) or physically tiring to the animal. Initial treatment of the coughing animal is aimed at eliminating the underlying cause and not suppressing the cough.

1. Antitussives decrease the severity and frequency of coughing.

a. Peripherally acting antitussives include anti-inflammatory drugs, mucolytics, and bronchodilators.

b. Central acting opioid and nonopioid drugs reduce the sensitivity of the cough center to afferent stimuli. The opioid cough suppressants may cause sedation, nausea, and constipation. (See Chapter 4 for more information about opioids.)

(1) Codeine—dogs and cats. One of the most effective with an antitussive effect that is much greater than its analgesic effect.

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