Inhalant delivery offers alternatives to treating respiratory disease

Q Please review inhalant therapy in dogs and cats.

A Dr. Leah A. Cohn at the 2006 American College of Veterinary Internal Medicine Forum in Louisville, Kentucky gave a lecture on inhalant delivery of medications in small animals. Some relevant points in this lecture are provided below.

Inhalant delivery of aerosolized medication offers a number of benefits including an enormous absorptive surface area across a permeable membrane, a low enzyme environment that result 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 and 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. In veterinary medicine, the literature on inhalant therapy is sparse, and what does exist focuses on aerosol drug delivery to horses rather than to dogs and cats. Regardless, aerosol delivery of medication has become popular for the treatment of dogs and cats with respiratory tract disease.

Although there are advantages 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 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 for use in humans. Some require purposeful respiration and breath holding. Adaptations of some devices facilitate their uses 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 tract 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

The basic types of aerosol delivery systems in common usage are nebulizers and metered-dose inhalers (MDI). In general, nebulizers deliver much smaller particles allowing deeper respiratory tract 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 use 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 (e.g., spinning-disc nebulizers and vibrating-mesh nebulizers) to improve delivery or modulate particle size. Nebulizers are available in portable sizes at a modest price, certainly suitable for use in veterinary hospitals and even practical for at-home use by owners (e.g., Nebulair Veterinary Portable Ultrasonic Nebulizer®, DVM Pharmaceuticals and many portable products for the human market). Nebulized liquid can be administered to dogs and cats by face mask, by tent, in a closed aquarium-like 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 animal.

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 mouthpiece, 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 about 10 percent of each dose reaches the airways). Obviously, dogs and cats can't use an 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 and 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 individual's mouth.

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 individual's inhalation through a reservoir containing a dry powder 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 dogs and cats than MDI attached to spacers.

Indications for nebulization

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. Sterile saline nebulization without antimicrobial drugs for 15-30 minutes at a time, administered three to four times per day is safe for the treatment of animals with bronchopneumonia.

It is common to include antimicrobials in nebulized solutions to treat severe bacterial pneumonia. There are drugs made especially for delivery by this route that do not contain potentially reactive additives or preservatives (e.g., Tobi®) but these preparations are prohibitively expensive.

Veterinarians have used inexpensive 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 is the aminoglycosides.

There are no well-established guidelines for dosing or administration of formulations of drugs not made for aerosol use in dogs and cats. 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 small percentage of animals 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, regard it as a complimentary therapy.

When nebulizers are used in the treatment of dogs and cats 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 after use in animals with respiratory tract infection. Nebulization of a nosocomial Pseudomonas species, 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. It is important to note that inhaled steroids take days or weeks to be effective, and thus should not be used for emergency 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 [e.g., fluticasone (Flovent)], short-acting bronchodilators [e.g., 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 [e.g., salmeterol (Serevent); fluticasone and salmeterol combination (Advair); formoterol (Foradil)]. Even when the drug is available as an MDI, not all MDIs fit the spacers typically used for dogs and cats [e.g., triamcinolone acetonide (Azmacort)]. It is important that the prescribing veterinarian is certain that the drug prescribed comes in an MDI that will work with the spacer device used.

Dr. Hoskins is owner of DocuTech Services. He can be reached at (225) 955-3252, fax: (214) 242-2200, or e-mail:jdhoskins@mindspring.com.