18
Drugs used in the management of
respiratory diseases
Philip Padrid and David B Church
INTRODUCTION
The term ‘respiratory disease’ includes any disorder of
the pulmonary tree, including infectious and noninfec-
tious disease(s) of the nasal cavity and sinuses, posterior
oropharynx, larynx, trachea, bronchi, lung parenchyma
and pleural cavity. This chapter will concentrate pri-
marily on the drugs used to treat respiratory disease in
dogs and cats in which the primary cause is not due to
infectious or parasitic agents. The reader is referred to
other chapters of this book for specific methods of treat-
ing viral, bacterial, fungal and parasitic infections of the
respiratory tract. Additionally, respiratory dysfunction
due to pulmonary congestion and edema as a result of
primary or secondary heart failure will also be covered
in other appropriate chapters.
CLINICAL SIGNS OF
RESPIRATORY DISEASE
Regardless of the cause, inflammation and/or obstruc-
tion of the respiratory tract results in a relatively small
number of clinical signs. These include sneezing, reverse
sneezing, coughing, gagging, nasal discharge, noisy
breathing, increased (rarely decreased) rate of breath-
ing, increased or decreased depth of breathing, lethargy
and exercise intolerance. Most respiratory disorders will
cause some combination of these signs to occur simul-
taneously. In order to make rational choices for the
treatment of both the signs and the underlying cause(s)
of these signs, it is helpful to briefly review the relevant
pathophysiology.
Pathophysiological regulation of
airway size
The diameter of an airway has a profound effect on the
amount of air that can travel through that airway as
well as the speed with which that air travels.
458
Ch018-S2858.indd 458
There are two important clinical messages:
1. decreased airway diameter results in increased
airflow velocity. This, in turn, causes a drop in
airway pressure
2. small changes in airway diameter result in
enormous changes in the amount of air that can
pass through that airway.
Many respiratory diseases cause airway narrowing from
edema, mucus formation or cellular infiltration. Normal
volumes of air may not be able to flow easily on a
breath-by-breath basis and the airways may be prone to
collapse. This phenomenon is one of the causes of noisy
breathing, tachypnea, sneeze, cough, lethargy and exer-
cise intolerance. Therefore, drug therapy that results in
an increase in airway diameter may minimize or even
abolish these clinical signs.
Airway diameter is also determined by physiological
bronchial tone mediated through nervous airway smooth
muscle innervation. In dogs and cats the primary effer-
ent system is parasympathetic and the major neurotrans-
mitter is acetylcholine.
The mechanisms involved in cholinergic bronchocon-
striction are complex and incompletely understood.
Intracellular effects depend in part on modifications of
intracellular levels of cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP).
The effects of these two second messengers are recipro-
cal; hence increased concentrations of one are
associated with decreased concentrations of the other.
Cyclic AMP is increased by β2-receptor stimulation and
decreased by activation of α-receptors. In contrast, acti-
vation of H1-receptors, muscarinic effects of acetylcho-
line and a variety of different inflammatory mediators
and increased intracellular Ca2+ concentrations all
increase cGMP levels.
Acetylcholine’s actions are mediated via a number
of mechanisms, which are not all cAMP or cGMP
dependent. These include increasing intracellular con-
centrations of inositol 1,4,5-triphosphate (ITP) and dia-
cylglycerol (DAG) as well as promoting calcium influx
11/19/2007 2:28:14 PM

through L-type calcium channels. The ITP effects are
thought to be responsible for the initial phase of bron-
chial smooth muscle contraction, mediated via a tran-
sient increase in intracellular calcium concentration
released from the sarcoplasmic reticulum. While this
process appears to be cAMP dependent, it has been pos-
tulated that a cholinergically mediated decrease in cAMP
is the cause of the increased intracellular ITP concentra-
tion. However, while this first phase may be cAMP
independent, the maintenance of bronchoconstriction
appears to involve both ITP- and DAG-modifying cAMP
levels through unknown mechanisms.
Acetylcholine-mediated basal airway tone is minimal
in dogs and results in only mild bronchoconstriction in
resting feline airways. However, unlike the dog, there
are at least five receptor types in feline airways that
respond to parasympathetic input. One receptor type,
the irritant receptor, is located beneath the respiratory
epithelium and has been found in cat airways as
far distally as the alveoli. The increased types and
distribution of ACh-responsive receptors are likely to
at least partly explain the severity of clinical signs
associated with feline bronchitis compared with canine
bronchitis.
Although resting airway tone in dogs is minimal,
canine airways are more responsive than feline airways
to acetylcholine. However, canine airways (in relation
to their body surface area) are enormous compared with
feline airways and changes in bronchomotor tone in
dogs result in relatively trivial clinical changes com-
pared with the cat.
The sympathetic system also mediates airway caliber
and tone. These actions are mediated via β1- and β2-
adrenergic bronchodilation and α1-adrenergic broncho-
constriction, as well as possibly α2-adrenergic reduction
of parasympathetic bronchoconstriction. Variations in
the density of β1- and β2-receptors within cat airways
contribute to the increased responsiveness of cat airways
to naturally occurring and drug-induced changes in
bronchomotor tone compared with the dog.
A third nervous system, the nonadrenergic, noncho-
linergic (NANC) system, further mediates bronchomo-
tor tone through various neurotransmitters, such as
vasoactive intestinal peptide.
BRONCHODILATOR DRUGS
The use of bronchodilators in various disease states is
based on the assumption that clinically significant bron-
choconstriction exists. The degree of resting broncho-
motor tone and the reactivity of airway smooth muscle
in response to different disease states and airborne
agents are species specific. For example, as previously
Ch018-S2858.indd 459
ADRENERGIC AGONISTS
mentioned, there is minimal bronchomotor tone in
healthy dogs at rest. In contrast, cats have a greater
degree of bronchomotor tone at rest that can be reversed
with vagolytic agents.
In general, bronchoconstriction is not an important
cause of clinical signs in dogs with bronchopulmonary
disease. For example, less than 15% of dogs with
chronic bronchitis have increased airway resistance (a
measure of increased bronchomotor tone) that can be
reversed with bronchodilator agents. In contrast, cats
develop naturally occurring and clinically significant
bronchoconstriction which in severe cases of allergic
inflammation can be life-threatening.
Bronchodilator drugs can be classified as β-receptor
agonists, methylxanthine derivatives and anticholiner-
gics. As mentioned above, adrenergic stimulation can
result in α1-adrenoreceptor mediated bronchial constric-
tion, α2-adrenoreceptor mediated bronchodilation,
probably through inhibition of cholinergic broncho-
constriction, or bronchodilation through activation of
β2-adrenoreceptors. The bronchodilatory effects of
β2-adrenoreceptors are mediated not only through
increasing cAMP concentrations but also, perhaps more
importantly, through a cAMP-independent pathway
that involves activation of a large-conductance calcium-
activated potassium channel. Activating this channel
allows an extracellular potassium efflux, increase in
transmembrane potential and hence a reduction in
calcium influx through the voltage-dependent L-type
calcium channels, thus resulting in bronchodilation.
ADRENERGIC AGONISTS
All adrenergic agonists have variable α- and β-receptor
affinity. In view of the distribution of α- and β-receptors,
nonselective β-receptor agonists such as isoprenaline
(isoproterenol) or mixed α- and β-receptor agonists
such as adrenaline (epinephrine) 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.
Aerosol delivery
Even when selective β2-agonists are used, the preferen-
tial activation of pulmonary β2-receptors may be
enhanced by inhalation of small doses of the drug in
aerosol form. This approach typically leads to rapid and
effective pulmonary β2-receptor activation with low sys-
temic drug concentrations.
Aerosol administration relies upon the delivery of
drug to distal airways, which in turn depends on the
459
11/21/2007 12:21:37 PM
 CHAPTER 18 DRUGS USED IN THE MANAGEMENT OF RESPIRATORY DISEASES
size of the aerosol particles and various respiratory
parameters such as tidal volume and inspiratory flow
rate. Even in such co-operative patients as humans, only
approximately 10% of the inhaled dose enters the lungs.
Recent studies in cats have demonstrated that passive
inhalation through a mask and spacer combination
(Aerokat®) is an effective method of delivering suffi-
cient medication to be clinically effective. Preliminary
studies and anecdotal evidence suggest that dogs may
be treated equally effectively using a similar system.
The two principal β2-agonists currently marketed in
preparations that can be readily and regularly used in
small animals are terbutaline sulfate and salbutamol
(albuterol) sulfate.
Terbutaline sulfate
Mechanism of action
Terbutaline is a selective β2-receptor agonist that pro-
duces relaxation of smooth muscle found principally in
bronchial, vascular and uterine tissues. The exact mech-
anism by which activation of β2-receptors results in
smooth muscle relaxation is poorly understood although
it seems certain to involve changes brought about by
increased intracellular cAMP. It has been postulated that
the elevated cAMP levels inactivate the enzyme respon-
sible for activating myosin. Since the inactive myosin is
unable to interact with actin, smooth muscle contrac-
tion cannot occur.
Formulations and dose rates
Terbutaline is available as a tablet, an elixir and an injectable prepara-
tion suitable for subcutaneous or intramuscular use. The dose rate
has been reported from as low as 0.01 mg/kg given subcutaneously
or intramuscularly up to 0.1–0.2 mg/kg/8 h for the dog and cat given
orally.
Pharmacokinetics
The pharmacokinetics of terbutaline in dogs and cats
have not been described. In humans, around 45% of an
oral dose is absorbed; peak bronchial effects occur
within 2–3 h and last approximately 8 h. When admin-
istered subcutaneously, there is a more rapid onset of
activity (15 min) with a peak effect after 30–60 min and
duration of 4 h. Approximately 60% of administered
terbutaline is excreted unchanged in the urine, while the
remainder undergoes hepatic conjugation to inactive
metabolites.
Adverse effects
● At usual doses, terbutaline has little effect on β1-
receptors so direct cardiostimulatory effects are
460
Ch018-S2858.indd 460
unlikely. However, terbutaline should always be
used with care in patients who may have increased
sensitivity to adrenergic agents – in particular,
patients with pre-existing cardiac disease, diabetes
mellitus, hyperthyroidism, hypertension and seizure
disorders.
● All β2-agonists may lower plasma potassium; hence,
in at-risk patients receiving long-term terbutaline
therapy, it may be prudent to monitor plasma potas-
sium levels. In clinical practice and experimentally, it
is rare to find β2-agonist associated hypokalemia in
dogs and cats.
Known drug interactions
● Terbutaline used with other sympathomimetics
increases the risk of adverse cardiovascular effects,
as does its concurrent use with digoxin, tricyclic
antidepressants and monoamine oxidase inhibitors.
These potential effects are more likely in patients
with pre-existing cardiac disease, especially hyper-
trophic cardiomyopathy.
● Use with various inhalation anesthetics may predis-
pose the patient to ventricular arrhythmias.
Salbutamol (albuterol) sulfate
Mechanism of action
Salbutamol (albuterol) is a selective β2-receptor agonist
with pharmacological properties similar to terbutaline.
Formulations and dose rates
Salbutamol is available as a tablet, syrup, as well as various inhalants.
The oral dose rate in the dog is 0.02 mg/kg/12 h. This dose should
be maintained for 5 days and if there has been no improvement and
no adverse effects, the dose may be increased to 0.5 mg/kg/8–12 h.
In animals that respond at this higher dose, the dose should be
reduced progressively until the lowest effective dose has been deter-
mined. However, because the inhaled form of salbutamol is now
available for use in veterinary practice, there is little advantage to
using the oral preparation.
The inhaled form of salbutamol comes as a single strength 17 g
metered dose inhaler and delivers 90 µg per actuation of the device.
Additionally, salbutamol can be included in discus or dry powder
forms with other inhaled medications, including fluticasone hydro-
chloride (Advair®). Currently, however, there is no practical method
to deliver the discus or powder form of the drug(s) to dogs and
cats.
Pharmacokinetics
The pharmacokinetics of salbutamol in dogs and cats
have not been studied. In humans, when administered
by inhalation, salbutamol produces significant broncho-
dilation within 15 min that lasts for 3–4 h. It is also
generally well absorbed orally and may have broncho-
11/19/2007 2:28:15 PM

dilatory effects for up to 8 h. Anecdotal experience with
this drug in clinical practice suggests a similar pharma-
cokinetic profile in cats. Salbutamol undergoes exten-
sive hepatic metabolism. After oral administration
approximately 58–78% of the dose is excreted in the
urine over 24 h, with 60% of the drug in an inactive
form.
Adverse effects
● Occasional but not common adverse effects include
skeletal muscle tremors and restlessness, which gen-
erally subside after 2–3 days.
● As with terbutaline, care should be exercised when
administering salbutamol to patients with pre-
existing cardiac disease, diabetes mellitus, hyperthy-
roidism, hypertension and seizure disorders.
Known drug interactions
Salbutamol’s potential interactions are similar to those
of terbutaline.
METHYLXANTHINES
The methylxanthines share several pharmacological
actions of therapeutic interest. They relax smooth
muscle, particularly bronchial smooth muscle, stimulate
the central nervous system and are weakly positive chro-
notropes and inotropes, as well as mild diuretics.
However, in small animal practice the methylxanthines
have been used primarily as bronchodilators.
Theophylline and aminophylline
Chemical structure
Caffeine, theophylline and theobromine are three
naturally occurring methylxanthines. While all three
alkaloids are relatively insoluble, the solubility can be
enhanced by the formation of complexes with a wide
variety of compounds. The best known of these com-
plexes is aminophylline, which is the ethylenediamine
complex of theophylline with differing quantities of
water of hydration. Each 100 mg of hydrous and anhy-
drous aminophylline contains 79 mg and 86 mg of
theophylline respectively. Conversely, 100 mg of theo-
phylline is equivalent to 116 mg of anhydrous amino-
phylline and 127 mg of hydrous aminophylline. When
dissolved in water, aminophylline readily dissociates to
its parent compounds.
Mechanism of action
Although theophylline produces bronchial smooth
muscle relaxation, importantly it is considered a less
potent bronchodilator than the β-agonists. Theophylline
Ch018-S2858.indd 461
METHYLXANTHINES
has also been credited with producing centrally medi-
ated increased respiratory effort at any given alveolar
PCO2, improved diaphragmatic contractility and
reduced diaphragmatic fatigue, mild increases in myo-
cardial contractility and heart rate, increased central
nervous system (CNS) activity, increased gastric acid
secretion and mild diuresis. These effects have not been
demonstrated in dogs or cats and must be recognized as
an extrapolation from other species.
A number of mechanisms have been proposed to
explain these various effects. These have included inhi-
bition of phosphodiesterases with a resultant increase in
intracellular cAMP, direct and indirect effects on intra-
cellular calcium concentration, uncoupling of intra-
cellular calcium concentration and muscle contractile
elements and competitive inhibition of adenosine
receptors.
Interestingly, at therapeutic concentrations of theoph-
ylline, only adenosine receptor blockade has been
reliably demonstrated. Consequently many investiga-
tors suggest that this is the most likely explanation for
theophylline’s varied effects. However, it should be
noted that, at present, the exact mechanism by which
theophylline causes bronchodilation is far from
resolved.
Formulations and dose rates
Because of theophylline’s relatively low therapeutic index and phar-
macokinetic characteristics, dose rates should be based on lean body
mass. The dose rate of theophylline varies depending on the prepara-
tion used. In standard preparations the recommended dose rate in
dogs is 10 mg/kg/6–8 h PO and cats 4 mg/kg/8–12 h PO. When using
sustained-release preparations, a dose of 20 mg/kg/12 h for dogs and
25 mg/kg/24 h for cats should be considered. Although there have
been reports of varied bioavailability with different proprietary forms
of sustained-release preparations, Theo-Dur® and Diffumal® have
both reliably been shown to have bioavailability greater than 95% in
dogs.
• The dose rate of aminophylline is 11 mg/kg/8 h in dogs PO and
5–6 mg/kg/12 h PO in cats
Pharmacokinetics
The pharmacokinetics of theophylline have been exten-
sively studied in a number of species. Because theophyl-
line is not water soluble it can only be given orally. After
oral administration peak plasma rates occur within
1.5 h; rate of absorption is limited principally by disso-
lution of the dosage form in the gut. Bioavailability in
both cats and dogs is generally >90% when nonsus-
tained-release preparations are used. However, sus-
tained-release preparations may have a more variable
bioavailability. One study in dogs suggested that
four different sustained-release preparations had bio-
availability varying from 30% to 76%; however, other
investigators found bioavailability to be greater than
461
11/19/2007 2:28:15 PM
 CHAPTER 18 DRUGS USED IN THE MANAGEMENT OF RESPIRATORY DISEASES
95% in studies using two of these four products. In
general, the anhydrous theophylline tablet is preferred.
Theophylline is only weakly protein bound (7–14%),
with a relatively low volume of distribution (0.82 L/kg
in dogs, 0.46 L/kg in cats). Because of this low volume
of distribution and theophylline’s poor lipid solubility,
it is recommended that obese animals be dosed on a lean
body mass basis. Additionally, a chronopharmacoki-
netic study in cats showed that evening administration
is associated with better bioavailability and fewer fluc-
tuations in plasma drug levels.
In humans, theophylline is mainly metabolized in the
liver. Reported elimination half-lives are 5.7 h in the
dog and 7.8 h in the cat. Renal clearance of parent
compound contributes only about 10% of total plasma
clearance. In humans there are marked variations in
plasma half-life between individuals and it seems likely
that similar variation exists in dogs and cats, although
to date this has not been investigated.
Adverse effects
● Although theophylline can produce CNS stimulation
and gastrointestinal disturbances, usually these
effects are associated with excessive dosing and
resolve with a dose adjustment.
● Seizures or cardiac arrhythmias may occur in severe
toxicity.
Known drug interactions
● Theophylline’s effects may be diminished by phenyt-
oin or phenobarbital and enhanced by cimetidine,
allopurinol, clindamycin and lincomycin.
● The effects of theophylline and β-adrenergic blockers
may be antagonized if they are administered
concurrently.
● Theophylline increases the likelihood of arrhythmias
induced by adrenergic agonists and halothane.
● Theophylline increases the likelihood of seizures
with ketamine.
ANTICHOLINERGICS
Mechanism of action
There are cholinergic nerve fibers within the brainstem at
the level of the nucleus ambiguous, as well as within the
vagus nerve via the dorsal motor nucleus. Nervous
impulses traverse through parasympathetic ganglia
within the airway wall; postganglionic nerve fibers inner-
vate the submucosal glands and airway smooth muscle.
When activated, the endings of these nerve fibers release
acetylcholine and can result in mucus secretion and
smooth muscle contraction (bronchoconstriction).
462
Ch018-S2858.indd 462
Additionally, there is cholinergic innervation of the
lung and this is mediated through three muscarinic
receptors (M1, M2, M3). Interestingly, the M2 receptor
is antagonistic in that stimulation of M2 receptors
causes inhibition of further acetylcholine release. Atro-
pine is the classic anticholinergic compound and blocks
muscarinic receptors nonselectively. Since concurrent
blockage of M2 and M3 receptors is likely to have
antagonistic effects on acetylcholine secretion, drugs
that selectively block activation of M3 receptors (tiotro-
prium bromide) have been developed. Interestingly,
while in humans drugs that block cholinergic pathways
are effective in the treatment of COPD, this class of drug
has not demonstrated similar efficacy in treating dogs
or cats with bronchial disease.
In the authors’ experience, the primary indication for
anticholinergic drug therapy in veterinary respiratory
medicine is to pretreat cats with existing bronchial
disease prior to anesthesia to decrease excessive mucoid
secretions that would otherwise result from tracheal
intubation. It may also be helpful as an adjunctive bron-
chodilator for patients with pre-existing asthma for
which bronchoscopy is planned.
TOPICAL ANTI-INFLAMMATORY
THERAPY
Oral and parenteral corticosteroids are commonly
used by veterinarians to treat a number of pulmonary
disorders in dogs and cats, including allergic rhinitis,
bronchitis, asthma and eosinophilic pneumonia (PIE
syndrome). This class of drugs is effective for this
purpose but the list of side effects is long and
ranges from annoying (increased urination) to life-
threatening (pancreatitis, diabetes mellitus). Inhaled
steroid medications have the advantage of significant
clinical efficacy without the systemic side effects of the
oral or parenterally administered medications. The most
commonly used inhaled corticosteroid is fluticasone
proprionate.
Fluticasone proprionate
Fluticasone proprionate is a synthetic corticosteroid
that has 18-fold greater affinity for the corticosteroid
receptor compared with dexamethasone, the reference
standard for corticosteroid potency. Similarly to oral
and parenteral corticosteroids, fluticasone activates the
glucocorticosteroid receptor present on virtually all cells
within mammalian systems. Binding of the steroid to
this receptor results in a new molecular complex that
itself binds to promoter-enhancer regions of target
11/19/2007 2:28:15 PM

genes, resulting in up- or downregulation of the gene
and its product. Fluticasone, like other corticosteroids,
acts to inhibit mast cells, eosinophils, lymphocytes, neu-
trophils and macrophages involved in the generation
and exacerbation of allergic airway inflammation by
transcriptional regulation of these target genes. Pre-
formed and newly secreted mediators including hista-
mine, eicosanoids, leukotrienes and multiple cytokines
are inhibited as well.
Fluticasone is a large molecule and acts topically
within the airway mucosa. Because there is poor absorp-
tion across gut epithelium there is minimal oral systemic
bioavailability, thus plasma levels do not predict thera-
peutic effects. This explains the lack of systemic side
effects but it also suggests that clinically effective absorp-
tion into the airway mucosa is delayed. Optimal clinical
effects therefore may not occur for 1–2 weeks.
Fluticasone has been used to treat cats with bronchial
asthma since at least 1993. The first systematic pub-
lished report of the use of this drug for this purpose was
in the year 2000. Since then, a number of manuscripts
have demonstrated the clinical effectiveness of flutica-
sone to treat dogs and cats with allergic rhinitis,
bronchitis and asthma (naturally occurring and experi-
mentally induced). There have been no controlled pub-
lished studies to determine the optimal dose or interval
for use of fluticasone in dogs or cats. However, there
are anecdotal reports (by one of the authors) that refer-
ence more than 500 small animal patients treated with
fluticasone over a period covering 1995–2006. Dosage
recommendations are therefore based on these anec-
dotal reports and are supported by more recent pub-
lished studies.
Formulations and dose rates
Inhaled corticosteroids come in multiple forms. However, only the
metered dose inhalers (MDI) combined with a spacer and mask appro-
priate for the size of the patient’s muzzle are currently suitable for
use in small animal patients. Fluticasone comes in three strengths:
44/110 and 220 µg per actuation. The authors have found that 44 µg
dosing twice daily does not consistently result in acceptable clinical
responses in either dogs or cats of any size. For cats and dogs less
than 12 kg, 110 µg given twice daily frequently results in clinical
responses equivalent to that achieved by administration of oral doses
of prednisone 5 mg PO BID. Dogs larger than 12 kg may need twice
this dose, or 220 µg inhaled BID.
The choice of spacer is clinically significant because the efficacy
of a spacer as a delivery device affects the amount of drug available
to the patient. Most mammalian species including dogs and cats have
a tidal volume of 10–20 mL inspired air/kg of bodyweight. Currently,
only the Aerokat® and Aerodawg® brand (Trudell Medical Inc, Ontario)
spacers have been designed specifically based on the tidal volume
characteristics of small animals. Using these spacer devices, dogs
and cats will inhale the majority of drug propelled into the spacer by
breathing 7–10 times through the spacer– mask combination after
Ch018-S2858.indd 463
ANTITUSSIVES
actuation of the MDI. As previously mentioned, it may take 1–2 weeks
to reach maximal clinical efficacy due to the large size of the molecule
and slow penetration into airway mucosa.
ANTITUSSIVES
Relevant pathophysiology
The cough reflex is complex, involving the central and
peripheral nervous systems as well as the smooth muscle
of the bronchial tree. Chemical or mechanical irritation
of the epithelium within bronchial mucosa causes bron-
choconstriction, which in turn stimulates cough recep-
tors located within the tracheobronchial tree. Afferent
conduction from these receptors occurs via the vagus
nerve to centers within the medulla that are distinct
from the actual respiratory center.
The drugs that can affect this complex mechanism are
quite diverse. For example, coughing as a result of bron-
choconstriction may be relieved by bronchodilators
acting simply to dilate airways, while other antitussive
agents act primarily on the peripheral or central nervous
system components of the cough reflex. Generally,
however, the most effective antitussives elevate the
threshold for coughing by poorly understood centrally
mediated mechanisms.
Clinical applications
Almost any respiratory tract disorder involving any
level of the large and small airways can result in cough-
ing. This should normally be viewed as a protective
physiological process resulting in clearance of thick and
tenacious secretions produced by chronic airway inflam-
mation. Thus, cough suppression as a single therapeutic
agent is relatively contraindicated when cough is associ-
ated with mucus production. In investigating any animal
with suspected respiratory disease, it is important
to establish if the animal gags, chokes or swallows
after coughing. If the answer to any of these questions
is yes, it is likely mucus is being produced and brought
to the caudal pharynx. In these cases, cough suppression
as a single treatment modality is likely to be
contraindicated.
However, once mucus production is diminished or
resolved, cough suppression may be desirable. Chronic
coughing tends to increase airway inflammation,
increasing the risk of a vicious cycle in which the cough
causes mucosal irritation. This can result in further
coughing. Consequently, cough suppression may be
particularly helpful for selected patients, including
dogs with tracheobronchial collapse or dogs recovering
from the acute phase of the kennel-cough complex.
463
11/19/2007 2:28:15 PM
 CHAPTER 18 DRUGS USED IN THE MANAGEMENT OF RESPIRATORY DISEASES
Additionally, there are cases when the cough is so frus-
trating for owners that euthanasia of the pet is being
considered. Cough suppression may be life saving in this
instance.
Typically, drugs used to suppress coughing are cate-
gorized as narcotic (opioid) or nonnarcotic (nonopioid).
Unfortunately, although many nonopioid antitussives
can be effective in experimental situations, these same
drugs are not predictably effective in naturally occurring
clinical situations. Consequently, in the authors’ opinion,
generally narcotic antitussives are needed to achieve
effective cough suppression.
NONOPIOID ANTITUSSIVES
Dextromethorphan hydrobromide
Mechanism of action
Dextromethorphan hydrobromide is a semisynthetic
derivative of opium that acts centrally to elevate the
cough threshold. It does not have addictive, analgesic
or sedative action and in usual doses does not produce
respiratory depression or inhibit ciliary activity.
Although dextromethorphan is the D isomer of the
codeine analog, and thus levorphanol, it binds to central
binding sites that appear to be distinct from standard
opioid receptors. The nonopioid nature of these sites
is reinforced by the inability of naloxone to reverse
dextromethorphan’s effects.
Formulations and dose rates
Dextromethorphan is generally marketed in over-the-counter formula-
tions (usually syrups or lozenges) combined with various antihista-
mines, bronchodilators and mucolytics. A dose of approximately
2 mg/kg PO has been suggested, although, as with most of the anti-
tussive agents, higher doses are often required. Antitussive effects
may persist for up to 5 h. In the authors’ experience, the effectiveness
of dextromethorphan is significantly less than that of the various
opioid antitussives. Its main advantage is its ease of availability and
lack of accountability to federal agencies for its use, although gener-
ally this is more than offset by its lack of clinical efficacy!
Pharmacokinetics
There appears to be no information available on the
pharmacokinetics of dextromethorphan in cats and
dogs. In humans, onset of action is 30 min.
Adverse effects
Adverse effects of dextromethorphan are confined to
CNS depression and this has only been reported at
extremely high doses.
464
Ch018-S2858.indd 464
OPIOID ANTITUSSIVES
Codeine phosphate
Mechanism of action
Codeine has extremely low affinity for standard CNS µ,
κ and δ opioid receptors. Its antitussive activity proba-
bly involves distinct codeine-specific receptors. Ligation
of these receptors reduces the sensitivity of the cough
center to afferent impulses.
Formulations and dose rates
Codeine phosphate is available as 30 mg and 60 mg tablets as well
as being present in many mixed analgesic preparations. Codeine
phosphate is a schedule II drug and is subject to the Controlled Sub-
stance Act of 1970 (USA). The starting antitussive dose has been as
low as 0.1–0.3 mg/kg/8–12 h and as high as 1–2 mg/kg/6–12 h.
Whatever the starting point, the dose may need to be increased to
achieve a satisfactory effect.
Pharmacokinetics
Because of its reduced first-pass hepatic metabolism in
comparison to other opioids, codeine has a high bio-
availability. Oral administration of codeine provides
around 60% of its parenteral efficacy. Once absorbed,
codeine is metabolized by the liver, with the largely
inactive metabolites excreted predominantly in the
urine.
In humans, approximately 10% of administered
codeine is demethylated to form morphine and both free
and conjugated forms of morphine can be found in the
urine of patients receiving therapeutic doses of codeine.
In humans, codeine’s plasma half-life is around 2–4 h.
Adverse effects
● Codeine is generally well tolerated, although
adverse effects are possible especially at higher dose
rates.
● Sedation is the most common side effect in the dog.
● CNS stimulation may be seen in cats.
● Constipation is common when codeine is given for
more than a few weeks.
Hydrocodone tartrate
Mechanism of action
Hydrocodone has increased antitussive properties com-
pared to codeine. In humans, it has been suggested that
hydrocodone may have twice the antitussive potency
of morphine. The mechanism of this effect seems to
be direct suppression of the cough center within the
medulla. Hydrocodone may also reduce respiratory
mucosal secretions through undetermined mechanisms.
11/19/2007 2:28:15 PM

Formulations and dose rates
The starting dose rate in dogs is 0.22 mg/kg/6–12 h PO. For dogs
with intractable cough (tracheal collapse, left mainstem bronchial
collapse due to enlarged left atrium) the dose of hydrocodone often
needs to be increased to 0.45–0.9 mg/kg/6–12 h. Hydrocodone is
marketed in combination with homatropine as both an elixir and tablet
formulations. The addition of homatropine may be intended to dis-
suade inappropriate use of the drug for pleasure and usually does not
cause significant untoward side effects in dogs or cats. In the authors’
experience this is the most effective and safe cough suppressant
available for use in the canine species.
Pharmacokinetics
In humans, hydrocodone is well absorbed orally, with a
serum half-life of 3.8 h. In dogs the antitussive effect
generally lasts between 6 and 12 h. Owners may be
instructed to note the duration of action in their pet.
Dosing intervals are then based on these observations.
Adverse effects
Adverse effects include:
● sedation
● constipation
● other gastrointestinal side effects including
borborygmus and diarrhea.
Dihydrocodeine tartrate
Mechanism of action
Dihydrocodeine also acts centrally to raise the cough
threshold. Its other CNS activities seem to be markedly
less than those of codeine.
Formulations and dose rates
Dihydrocodeine is marketed as an elixir, which is relatively palatable
and well absorbed. A starting dose rate of 2 mg/kg/8–12 h PO is
recommended, although higher doses may be required for satisfactory
therapeutic effect.
Pharmacokinetics
In humans, dihydrocodeine is well absorbed after oral
administration. It has a serum half-life of about 3.8 h
and its antitussive effects last for 4–6 h. The antitussive
action appears to persist for 6–12 h. Unfortunately there
is no information available on the pharmacokinetics of
dihydrocodeine in dogs.
Adverse effects
Although constipation has been reported in humans, it
is an unusual occurrence and adverse effects are gener-
ally extremely uncommon.
Ch018-S2858.indd 465
MUCOLYTICS
Butorphanol
Mechanism of action
Butorphanol is a very effective antitussive as well as an
analgesic. In dogs it is 100 times more potent as a cough
suppressant than codeine and four times more potent
than morphine. It has been shown to elevate the CNS
respiratory center threshold to carbon dioxide but,
unlike other opioid agonists, it does not suppress respi-
ratory center sensitivity. In the authors’ experience
butorphanol is most helpful as an antitussive given
parenterally to treat acute intractable cough.
Formulations and dose rates
The antitussive dose of butorphanol in dogs is 0.55–1.1 mg/kg/6–
12 h orally or 0.055–0.11 mg/kg/6–12 h subcutaneously.
Pharmacokinetics
Butorphanol is well absorbed orally but a significant
first-pass effect results in less than 20% appearing in the
systemic circulation. Peak serum levels are attained at
1 h in dogs when the drug is given subcutaneously. The
half-life is less than 2 h and duration of action is
approximately 4 h in the canine species. It is well dis-
tributed and in humans approximately 80% protein
bound. Butorphanol is extensively metabolized in the
liver and predominantly excreted in the urine.
Adverse effects
Adverse effects include:
● sedation
● anorexia
● occasionally diarrhea.
MUCOLYTICS
Relevant pathophysiology
Mucus is a normal protective coating of the respiratory
system from the nasal cavity through to the larger bron-
chioles. It acts as a barrier to infectious and irritating
particles. It also provides airway humidification and
participates in maintaining an ideal environment for
ciliary movement. Mucus is produced by submucosal
glands and goblet cells within the surface epithelium of
airways. Although submucosal glands produce a far
greater volume of mucus compared to the goblet cells,
both of these mucus-secreting tissues respond to direct
contact with a variety of substances such as smoke,
sulfur dioxide and ammonia. Direct innervation is pre-
dominantly cholinergic.
465
11/19/2007 2:28:15 PM
 CHAPTER 18 DRUGS USED IN THE MANAGEMENT OF RESPIRATORY DISEASES
The viscosity of pulmonary mucus secretions depends
on the concentration of mucoproteins and DNA. Mucus
chains are cross-linked by disulfide bonds and it is this
chemical bond that is affected by some mucolytic agents
(see N-acetylcysteine below). The feline species is some-
what unique in forming sialic acid residues within the
mucus strands and this imparts a particularly viscous
nature to feline mucus. While mucoprotein is the main
determinant of viscosity in normal mucus, in purulent
inflammation the mucus concentration of DNA increases
(because of increased cellular debris) and so does its
contribution to viscosity. Importantly, although water is
incorporated into the mucus gel matrix during mucus
formation, topically applied water is not absorbed into
the already formed mucus plug.
Clinical applications
Dogs and cats with lower airway inflammatory diseases
will produce large amounts of relatively viscous inflam-
matory exudate and mucus which is firmly attached to
the lining of bronchioles and bronchi. By effectively
increasing bronchial wall thickness, this thick adherent
mucus can exacerbate the ‘lumen-narrowing’ effects of
bronchial constriction, enhance the overall inflammatory
process and potentiate persistent coughing. In this situa-
tion, mucolytic therapy has theoretical value in facilitat-
ing resolution of the inflammatory airway disease.
In general, mucolytic drugs act by altering mucus
structure through changes in pH, direct proteolysis and/
or disruption of disulfide bond linkages. The two most
frequently prescribed mucolytic drugs in veterinary
practice are described below. It is also worth remember-
ing that normal saline, directly administered to the
airways by nebulization, is an effective mucolytic and
expectorant.
Bromhexine hydrochloride
Bromhexine hydrochloride is a synthetic derivative of
the alkaloid vasicine.
Mechanism of action
Bromhexine decreases mucus viscosity by increasing
lysosomal activity. This increased lysosomal activity
enhances hydrolysis of acid mucopolysaccharide poly-
mers, which significantly contribute to normal mucus
viscosity. It should be remembered that, in purulent
bronchial inflammation, bronchial mucus viscosity is
more dependent upon the large amount of DNA present.
As bromhexine does not affect the DNA content, its
mucolytic action is limited in these situations.
It has also been suggested that bromhexine increases
the permeability of the alveolar–capillary barrier, result-
ing in increased concentrations of certain antibiotics
in luminal secretions. Furthermore, over time (2–3 d),
466
Ch018-S2858.indd 466
bromhexine results in a significant increase in immuno-
globulin concentrations and a decline in albumin and
β-globulin concentrations in respiratory secretions. The
increased immunoglobulins are IgA and IgG; IgM levels
remain unchanged. It has been hypothesized that because
of these effects concurrent administration of brom-
hexine and an antimicrobial agent will facilitate treat-
ment of infectious tracheobronchitis.
Formulations and dose rates
The mucolytic dose of bromhexine hydrochloride in dogs and cats is
2 mg/kg/12 h PO for 7–10 d, then 1 mg/kg/12 h for a further
7–10 d.
Pharmacokinetics
Following oral administration, bromhexine is rapidly
absorbed, with peak plasma levels being reached within
1 h. As it is lipophilic, it is rapidly redistributed, under-
goes extensive hepatic metabolism and is excreted via
the urine and bile.
Adverse effects
Adverse effects to bromhexine are extremely
uncommon.
Acetylcysteine
Acetylcysteine is the N-acetyl derivative of the naturally
occurring amino acid L-cysteine.
Mechanism of action
When administered directly into airways, acetylcysteine
reduces viscosity of both purulent and nonpurulent
secretions. This effect is thought to be a result of the
free sulfhydryl group on acetylcysteine reducing the
disulfide 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 increases with increasing pH.
Formulations and dose rates
Mucolytic
For effective mucolytic activity, an acetylcysteine solution should be
nebulized and administered directly to the respiratory mucosa as an
aerosol. The dose rate in dogs and cats is 5–10 mg/kg for 30 min
every 12 h. Additionally, there is at least one report of improved gas
exchange in dogs with experimentally induced bronchoconstriction
treated with oral acetylcysteine.
Acetylcysteine is available as 10% and 20% solutions of the sodium
salt in various sized vials. This solution can be readily used in a nebu-
lizer undiluted, although dilution with sterile saline will reduce the risk
of reactive bronchospasm.
11/19/2007 2:28:15 PM

Pharmacokinetics
When given orally, acetylcysteine is well absorbed; when
given by nebulization directly into the respiratory tract,
most acetylcysteine is involved in the sulfhydryl-
disulfide reaction and the remainder is absorbed. The
absorbed drug is metabolized via deacetylation to cys-
teine in the liver.
Adverse effects
Unfortunately, acetylcysteine appears to irritate respira-
tory tract epithelium and many dogs and cats develop
cough and/or bronchoconstriction when acetylcysteine
is administered directly into the respiratory tract. Con-
sequently, its use in animals with bronchoconstrictive
airway disease must be carefully monitored.
Known drug interactions
Solutions of acetylcysteine are incompatible with:
● amphotericin B
● ampicillin sodium
● erythromycin lactobionate
● tetracycline and oxytetracycline
● hydrogen peroxide.
EXPECTORANTS
Expectorants are drugs used to produce an increased
volume of respiratory secretions that can theoretically
be coughed out more easily. Although drugs in this class
are used in an enormous number of over-the-counter
medications, a Food and Drug Administration advisory
review panel found no well-controlled studies that doc-
umented the effectiveness of expectorants in managing
chronic obstructive pulmonary disease (COPD) in man.
Likewise, there are no current data available to suggest
that expectorants are effective adjunctive treatments for
dogs and cats with disorders of the respiratory tract.
However, because this class of drug is used with such
regularity, a brief discussion is appropriate.
Guaifenisin
The most commonly prescribed expectorant is guaifeni-
sin. An older name for this drug is glycerol guaiacolate;
it was isolated from guaiac resin in 1826. When given
in large amounts, guaifenisin acts as an emetic; it is
likely that it stimulates a gastropulmonary vagal reflex.
It may also be absorbed into bronchial mucosal glands
and exert a direct mucotropic effect.
The dose required to stimulate production of mucus
and respiratory tract secretions is probably equivalent
to the dose needed to produce emesis; this is far higher
than the 400–1600 mg/d range of dosing most com-
monly prescribed. Thus, at doses recommended to treat
Ch018-S2858.indd 467
ANTILEUKOTRIENES
humans with COPD the effect of guaifenisin is likely
equivalent to placebo.
ANTILEUKOTRIENES
Clinical applications
Leukotrienes belong to a family of inflammatory media-
tors that are derived from arachidonic acid and are
known collectively as eicosanoids. Arachidonic acid is
metabolized to various prostaglandins and thrombox-
anes through the action of cyclo-oxygenase as well as
various leukotrienes through the action of the lipoxy-
genase system.
The 5-lipoxygenase enzyme catalyzes the conversion
of arachidonic acid to 5-hydroperoxy-eicosatetraenoic
acid (5-HPETE) and then to leukotriene A4 (LTA4).
LTA4 is then converted to LTB4 or conjugated to LTC4.
LTC4 is converted to LTD4 and this is metabolized to
LTE4. The leukotrienes LTC4, LTD4 and LTE4 are col-
lectively known as the cysteinyl leukotrienes and play
an important role in airway inflammation. They produce
mucus hypersecretion, increased vascular permeability
and mucosal edema, induce potent bronchoconstriction
and act as chemoattractants to inflammatory cells, par-
ticularly eosinophils and neutrophils.
The cysteinyl leukotrienes act via two types of cell
surface receptor: cys-LT1 and cys-LT2. While the cys-LT2
receptor is mainly responsible for the effects of cysteinyl
leukotrienes on pulmonary blood vessels, cys-LT1 recep-
tors mediate most of the effects of cysteinyl leukotrienes
on airways.
Zafirlukast, montelukast, zileuton
Mechanism of action
All three products are competitive, highly selective and
potent oral inhibitors of production or function of
LTC4, LTD4 and LTE4. Specifically, zileuton blocks leu-
kotriene biosynthesis by inhibiting production of the
5-lipoxygenase enzyme while both montelukast and zaf-
irlukast block adhesion of leukotrienes to their common
leukotriene receptor (cys-LT1).
In man, leukotrienes inhibit asthmatic responses to
allergen, aspirin, exercise and cold dry air. Additionally.
leukotriene blockade has been shown in many clinical
trials to decrease the amount and frequency of admin-
istration of corticosteroids in steroid-dependent human
asthmatics.
Few studies have investigated the role of leukotrienes
in canine or feline airway disease. Because dogs do not
develop naturally occurring asthma as do cats, the few
studies that have been done have focused on feline
airways. LTE4 is found in increased concentrations in
urine of asthmatic humans and is a commonly used
467
11/19/2007 2:28:16 PM
 CHAPTER 18 DRUGS USED IN THE MANAGEMENT OF RESPIRATORY DISEASES
marker for increased production of LTC4 and LTD4 in
people with asthma. No such increase in urinary LTE4
was found in 20 cats with signs of bronchial disease or
cats with experimentally induced asthma. More recently,
in another experimental model of feline asthma, no
increase in cysteinyl leukotrienes was found in either
urine or bronchoalveolar lavage fluid after challenge
exposure to sensitizing antigen. Additionally, zafirlukast
did not inhibit airway inflammation or airway hyperre-
activity in this feline asthma model. There is no current
evidence that drugs that affect leukotriene synthesis or
receptor ligation will play a significant role in the treat-
ment of feline or canine respiratory disease.
Formulations and dose rates
Drugs that block leukotrienes are available in pill form. There is at
least one author who claims efficacy in treating feline asthma with
zafirlukast (1–2 mg/kg BID) and montelukast (0.5–1.0 mg/kg SID).
Pharmacokinetics
The pharmacokinetics of these drugs in dogs and cats
have not been reported. In humans, they are well
FURTHER READING
Barnes PJ, Belvisi MG, Mak JC et al 1995 Tiotropium bromide, a novel
long-acting muscarinic antagonist for the treatment of obstructive
airways disease. Life Sci 56(11-12): 853-859
Bjermer J 2001 History and future perspectives of treating asthma as a
systemic and small airways disease. Respir Med 95(9): 703-719
Boothe DM 2004 Drugs affecting the respiratory system. In: King LG
(ed.) Respiratory disease in dogs and cats. WB Saunders, St Louis,
MO, pp 229-252
Dye JA, McKiernan BC, Jones SD et al 1990 Chronopharmacokinetics of
theophylline in the cat. J Vet Pharmacol Ther 13(3): 278-286
Kirschvink N, Leemans J, Delvaux F et al Bronchodilators in
bronchoscopy-induced airflow limitation in allergen-sensitized cats.
J Vet Intern Med 19(2): 161-167
Kirschvink N, Leemans J, Delvauz F et al 2006 Inhaled fluticasone
reduces bronchial responsiveness and airway inflammation in cats
with mild chronic bronchitis. J Feline Med Surg 8(1): 45-54
Norris CR, Decile KC, Berghaus LJ et al 2003 Concentrations of
cysteinyl leukotrienes in urine and bronchoalveolar lavage fluid of
cats with experimentally induced asthma. Am J Vet Res 64(11):
1449-1453
468
Ch018-S2858.indd 468
absorbed orally, although the presence of food can
reduce absorption by up to 60%. They are highly
protein bound, extensively metabolized by the liver and
undergo predominantly biliary excretion.
Adverse effects
● As only limited experience of these drugs in dogs and
cats is available, the prevalence, type and severity of
adverse reactions associated with their administra-
tion cannot be documented.
● In humans, leukotriene receptor antagonists have
occasionally been associated with elevated hepatic
enzyme levels, although active hepatic disease is
uncommon. Human case reports have also suggested
a rare association between the leukotriene receptor
antagonists and Churg–Strauss syndrome. This is a
rare condition involving vasculitis-associated asthma,
eosinophilia and pulmonary infiltrates. The cause
and effect association remains controversial, as most
of the affected patients were receiving steroids prior
to starting leukotriene receptor antagonist therapy.
Consequently, it seems plausible that most of the
cases were actually Churg–Strauss syndrome sup-
pressed by the oral steroids, which became unmasked
when the steroids were withdrawn.
Padrid PA 2000 Feline asthma. Vet Clin North Am Small Anim Pract
30(6): 1279-1293
Padrid PA 2006 Use of inhaled medications to treat respiratory
diseases in dogs and cats. J Am Anim Hosp Assoc 42(2): 165-169
Padrid PA, Hornof WJ, Kurpershoek CJ, Cross CE 1990 Canine chronic
bronchitis. A pathophysiologic evaluation of 18 cases. J Vet Intern Med
4(3): 172-180
Petruska JM, Beattie JG, Stuart BO et al 1997 Cardiovascular effects
after inhalation of large doses of albuterol dry powder in rats,
monkeys and dogs: a species comparison. Fundam Appl Toxicol
40(1): 52-62
Reinero CR, Byerly JR, Berghaus RD et al 2005 Effects of drug
treatment on inflammation and hyperreactivity of airways and on
immune variables in cats with experimentally induced asthma. Am J
Vet Res 66(7): 1121-1127
Ueno O, Lee LN, Wagner PD 1989 Effect of N-acetylcysteine on gas
exchange after methacholine challenge and isoprenaline inhalation
in the dog. Eur Respir J 2(3): 238-246
11/19/2007 2:28:16 PM