Inhalant drug therapy (Proceedings)

Inhalant delivery of aerosolized medication offers a number of theoretical benefits including an enormous absorptive surface area across a permeable membrane, a low enzyme environment that results in little drug degradation, avoidance of hepatic first-pass metabolism, and reproducible absorption kinetics. When the target of inhaled medications is the respiratory tract itself, additional benefits include the potential for a high drug concentration directly at the site of disease with minimization of systemic toxicity, often at a fraction of the dose required if the same drug was administered through a systemic route. Because of these advantages, inhalant delivery of medication has gained widespread use for the treatment of airway diseases in people. There is an enormous body of evidence in the medical literature regarding inhalational drug therapy in people. More recently, efforts have been made to evaluate the role for aerosol delivery of medication for the treatment of dogs, and especially cats, with respiratory disease.

Although there are benefits to inhalant drug delivery, there are difficulties in using this route as well. Respiratory defenses are efficient at preventing particulates from reaching the lower airways so it should come as no surprise that only a small proportion of the administered medication reaches the lower airways; a significant amount of drug is lost in the delivery device or deposited in the oropharynx. Another difficulty is that most aerosol drug delivery devices are designed to be used by humans on a voluntary basis and some require purposeful respiration and breath holding. Adaptations of some devices facilitate their use in animals, and modified systems are now marketed for dogs and cats. Drug delivery by the aerosol route depends in part of respiratory depth and rate, tidal volume, and airflow rates, yet all of these may be negatively impacted by respiratory disease. Additionally, not all drugs are suitable for aerosol delivery, and drugs themselves (or preservatives contained in the drug preparation) may cause airway irritation and possible bronchoconstriction potentially worsening respiratory compromise.

Aerosol delivery systems

There are two very basic types of aerosol delivery systems in common usage; nebulizers and metered dose inhalers (MDI). The two are quite distinct devices, and have distinct uses. In general, nebulizers deliver much smaller particles allowing deeper respiratory penetration and provide fluid along with drug. MDI devices deliver drug primarily to the larger airways. There are more than 30 drugs available as MDI, including anti-inflammatory drugs and bronchodilators.

Nebulizers utilize compressors to generate relatively high air pressures and flow rates. Generally, there is a source of compressed air or oxygen, a well into which fluid/drug can be placed, and a baffle which when hit by the drug causes the creation of small particles. The basic nebulizer types include jet nebulizers and ultrasonic nebulizers. Modifications exist (eg, spinning disc nebulizers, vibrating mesh nebulizers) to improve delivery or modulate particle size. Nebulizers are available in portable sizes of a modest price, certainly suitable for use in veterinary hospitals and even practical for at-home use by owners. Cost can begin at under $100 for a good nebulizer unit. Veterinary specific nebulizer units are available for purchase (eg, Trudell Medical). Nebulized liquid can be administered to dogs and cats by face mask, by tent, in a closed aquarium type container into which the animal is placed, or into a tracheotomy tube. Any of these should be suitable for airway humidification via saline nebulization. In general, the more removed the particle generator is from the respiratory tract the more drug would be expected to be lost outside of the respiratory tract. For this reason, administration of drugs via nebulization would likely be more effective by mask than when simply administered into a tank containing the pet.

MDI are designed for at-home administration of aerosolized drugs and are the preferred routine route of delivery for glucocorticoid and bronchodilator medications in people with asthma. Particles delivered by MDI are larger than those created by nebulization, and thus do not penetrate as deeply into the respiratory tract. A traditional MDI consists of a mouthpiece and an actuator (holder) into which a canister of medication is inserted. Manually depressing the canister (actuation) results in the release of a single dose of medication (sometimes called a "puff"). People shake the canister, exhale deeply, insert the mouth piece, and simultaneously depress the canister and inhale as deeply as possible. They then hold their breath for as long as possible, exhale, and rinse the mouth and spit to remove the majority of the drug deposited in the oropharynx (only ~10% of each dose reaches the airways). Obviously, dogs and cats can't use a MDI in this way. Spacers devices designed to fit the MDI have allowed their adaptation for use in animals. Several types of spacers are available, from simple tubes inserted between the MDI and the mouth/nose to holding chambers with one-way valves activated by inhalation. Spacers were designed for young children or others with less than ideal coordination so that there is no requirement for simultaneous depression of the canister and inhalation. The spacer also has the advantage of allowing the largest particles to fall out and not enter the patient's mouth. In people, spacers actually improve drug delivery by ~10%, nearly doubling the amount of drug reaching the target site.

Until recently, most MDI used chlorofluorocarbons as propellants. Concerns about the ozone layer have led to new technologies, including alternate propellants and the use of dry powder inhalers (DPI). The DPI devices contain no propellant, but rely on the patient's inhalation through a reservoir containing the dry power dose. The most common types of DPIs are "discus" inhalers and "turbohalers". Because they do not use a spacer device and require a voluntary inhalation of a minimum force to deliver drug these devices may be less useful for small animal patients than MDI attached to spacers. The change to newer formulations of MDI has dramatically increased the cost of some medications formerly available as inexpensive generic prepeartions.

Indications for nebulization

In small animal medicine, the predominant use of nebulizers has been the treatment of respiratory infection. Nebulizers have long been used to provide airway humidification or to administer antimicrobials directly into the respiratory tract. Mucolytic agents (e.g., N-acetylcysteine) have also been nebulized to treat animals with respiratory infection, although the author advices against this practice until more evidence of safety and efficacy are available (I have observed adverse effects after such therapy). Sterile saline nebulization without antimicrobial drugs for 15-30 minutes at a time, administered 3-4 times per day, is safe for the treatment of animals with bronchopneumonia. Although there are no scientific studies to demonstrate utility it is the author's impression that this is a useful therapy.

In people, it is common to include antimicrobials in nebulized solutions to treat severe bacterial pneumonia, particularly in patients with compromised defenses such as in patients with cystic fibrosis. There are drugs made especially for delivery by this route which do not contain potentially reactive additives or preservatives (e.g., Tobi®) but these preparations are prohibitively expensive. Veterinarians have used drugs made for parenteral administration in nebulized solutions for the treatment of pneumonia or other respiratory infections, including Bordetella bronchiseptica. Not all liquid antibiotics would be suitable for nebulization. The most frequently used class of antibiotics for nebulization are the aminoglycosides.

There are no well established guidelines for dosing or administration of formulations of drugs not made for aerosol use in veterinary patients. Typically, the dose that would be used systemically of a drug such as gentamicin or amikacin is diluted in saline to be delivered over a single 15-30 minute session with the nebulizer. It should be expected that a percentage of patients, perhaps 5 to 10%, may experience bronchoconstriction in response to such therapies. Pretreatment with bronchodilators may minimize potential reaction to drug carriers and improve drug delivery by the aerosol route. Bronchodilators may be administered by parenteral routes 15 minutes prior to nebulization or via an initial period of nebulization with the bronchodilator added directly to the nebulized fluid before the addition of the antimicrobial drug. Delivery of antimicrobials should not replace systemic antimicrobials in animals with pneumonia. Instead, it should be regarded as a complimentary therapy.

Bronchodilator drugs are often made for nebulization. Albuterol comes as a 0.5% solution for inhalaltion (5 mg/ml) or the premixed 2.5 mg/3 ml solution. The concentrated drug must me diluted in about 3 ml sterile saline before use. A dose for dogs and cats has not been established but the dose for children is 0.1 to 0.15 mg/kg up to a maximum of 2.5 mg given as often as four times daily.

When nebulizers are used in the treatment of pets with contagious respiratory disease, the device itself must be kept meticulously clean to avoid causing iatrogenic respiratory infection. Extreme care should be given to cleaning, and disposable parts of the device should be disposed of when after animals with respiratory infection. Nebulization of a nosocomial Pseudomonas, for instance, could have devastating consequences for an animal with compromised respiratory function.

Indications for MDI

Metered dose inhalers (MDI) are the preferred route of delivery for most asthma medications in people, and they have been advocated for the treatment of feline bronchopulmonary diseases including asthma as well as for the treatment of dogs with chronic bronchitis or related airway disease. The use of inhaled steroids may be particularly helpful in minimizing systemic effects of glucocorticosteroids in asthmatic cats with co-morbid conditions such as diabetes mellitus or congestive heart failure. For any pet, concomitant use of inhaled and systemic steroids may allow minimization of systemic dosages. It is important to note that inhaled steroids take days or weeks to be effective, and thus should not be used for emergent treatment of asthmatic cats. Albuterol delivery by MDI can be useful during exacerbations of asthma, but should not replace parenteral administration of bronchodilators for cats in asthmatic crisis.

A variety of respiratory drugs are available as MDI, including corticosteroids (eg, fluticasone (Flovent)), short acting bronchodilators (eg, albuterol (Ventolin, Proventil)), and non-steroidal anti-inflammatory drugs such as cromolyn or nedocromil. Some inhaled medications (including most long-acting bronchodilators and combination steroid/bronchodilators) come as DPI instead of MDI and are therefore not as useful in dogs and cats (eg, salmeterol (Serevent); fluticasone and salmeterol combination (Advair); formoterol (Foradil)). Even when the drug is available as a MDI, not all MDI fit the spacers typically used for dogs and cats (eg, triamcinolone acetonide (Azmacort)). It is important that the prescribing veterinarian is certain that the drug prescribed comes in a MDI that will work with the spacer device used by the patient.

There are spacer devices made specifically for veterinary patients (eg, Aerokat®; aerokat.com; Nebulair Feline Mask, Small Animal Aerosol Chamber®, DVM Pharmaceuticals), or devices for people can be adapted for veterinary use. The devices for humans can be purchased OTC from any pharmacy. Face masks can be purchased (anesthetic masks ~$40) or fashioned. The MDI fits directly in one end of the spacer. To administer a dose, the animal is turned so that the head faces away and the tail faces into the person delivering the drug. The MDI is shaken, the face mask fitted over the animals face, and the canister depressed (the canister can be depressed immediately before placement of the mask if the noise scares the pet, especially when using spacers with appropriate one-way valves). The animal is then allowed to breathe into the mask for 7 to 10 breaths. In the author's experience, few owners have trouble administering the inhaled medication in this fashion.

Efficacy of aerosol drug delivery in small animals

Bordetella bronchiseptica is susceptible to aminoglycosides delivered directly onto the respiratory epithelium, and such administration of aminoglycosides results in little if any systemic drug absorption. A published abstract suggests better recovery of dogs with kennel cough treated with nebulized aminoglycosides but this study lacked a control population and there was no confirmation of bacterial infection. There is only a single published study demonstrating the ability to deliver particles to the lower airways in conscious, unsedated cats via aerosol, and this study used a nebulizer device designed to create smaller (and therefore more deeply penetrable) particles than would a MDI. Inhaled steroids (flunisolide 250 ug BID) reduced eosinophil percentage in cats with experimentally induced asthma but did not effect allergen specific IgE, airway hyperresponsivness, or blood lymphocyte phenotype. A much lower doses of steroid (44 ug fluticasone BID) was as effective as either 110 or 220 ug of fluticasone BID in reduction of experimentally induced asthma eosinophilic airway inflammation in cats in another study. Other studies demonstrated less endocrine effect with inhaled vs. oral steroids in cats and dogs (respectively) but did not evaluate therapy of any disease state. Inhaled steroids have been used with success in the treatment of dogs which chronic bronchitis although these treatments were not controlled trials. Salmeterol, salbutamol, and ipratropium bromide or a combination of these drugs were able to reduce muscarinic-induced bronchospasm in healthy cats but have not been evaluated in cats with bronchopulmonary disease. Because of the questions still surrounding efficacy of drug delivery by aerosol, these drugs should generally be used as adjuncts in the treatment of animals with moderate to severe clinical signs. Once disease is relatively well controlled, inhaled therapies may replace other means of drug administration (note – the exception is delivery of antimicrobials, where inhaled therapies should never replace systemic therapies).

Aerosol delivery of other therapies

Other uses for inhalation therapy include treatment of lung cancer and systemic disease. Several reports describe the use of aerosolized drug delivery with chemotherapeutic or immunomoduling drugs in the treatment of spontaneous primary and metastatic cancers in dogs. Dogs have also been used as a model in the development of insulins to be delivered via a needle-free aerosol (Exubera®, Pfizer, Nektar). Small animals have been used as models for other aerosol therapies, including treatment aimed at cardiovascular and hemodynamic perturbations (eg, inhaled nitric oxide for pulmonary hypertension), vaccination, or even gene therapy. As delivery systems are developed specifically for animal patients, and as our knowledge of the efficacy of this system of drug delivery grows, we are likely to use more and more inhalational therapy in small animal patients.

Suggested readings

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Cherrington AD, et al. Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection. Diabetes 2004 53:877-881.

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Cohn LA. Inhalant therapy: Finding its place in small-animal practice. Vet Med. 104(7):336-341, 2009.

Cohn LA, DeClue AE, Cohen RL, Reinero CR. Effects of fluticasone propionate dosage in an experimental model of feline asthma. J Feline Med Surg, In Press, 2010.

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Khanna C, et al. Interleukin-2 liposome inhalation therapy is safe and effective for dogs with spontaneous pulmonary metastases. Cancer 1997;79:1409-1421.

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Labiris NR, et al. Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003;56:600-612.

Laube BL. The expanding role of aerosols in systemic drug delivery, gene therapy, and vaccination. Respir Care 2005;50:1161-1176.

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Reinero CR, et al. Inhaled flunisolide suppresses the hypothalamic-pituitary-adrenocortical axis, but has minimal systemic immune effects in healthy cats. J Vet Intern Med 2006;20:57-64.

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