Drugs Used in the Management of Respiratory Diseases

World Small Animal Veterinary Association World Congress Proceedings, 2006

David Church
Professor, Department of Veterinary Clinical Science, The Royal Veterinary College

North Mymms, Hatfield, Hertfordshire, UK

Respiratory diseases in dogs and cats can be classified into respiratory problems
brought about as a result of a specific abnormality of the respiratory system; so
called primary respiratory disease, and bronchopulmonary problems which occur as
a consequence of heart failure; so called secondary respiratory disease. This
section will concentrate predominantly on considerations regarding the treatment of
non-infectious aspects of primary respiratory diseases. This includes agents used to
facilitate bronchodilation, to reduce coughing and various expectorants and
mucolytics.
In order to understand the indications for, and action of, various drugs used in the
treatment of respiratory disease an understanding of normal respiratory physiology is
important and these considerations will be dealt with in the relevant sections.
Bronchodilators
Relevant Pathophysiology

Physiological bronchial tone is mediated by three neuroendocrine systems:

1.  The parasympathetic system, the dominant efferent pathway in animals, which
provides the baseline tone of mild bronchoconstriction that characterizes the
normal respiratory tract.
2.  The sympathetic system which mediates these inherent bronchoconstrictive
effects through β2-adrenergic-mediated bronchodilation and α1-mediated
bronchoconstriction as well as possibly α2-mediated reduction of
parasympathetic bronchoconstriction.
3.  The non-adrenergic, non-cholinergic (NANC) system which apparently further
mediates bronchodilation through various neurotransmitters such as
vasoactive intestinal peptide.
The mechanisms involved in cholinergic bronchoconstriction 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 secondary messengers are
reciprocal; 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 α1-adrenergic receptors. In contrast a variety of different
inflammatory mediators, activation of H1 receptors, increased intracellular Ca
concentrations and muscarinic effects of acetylcholine increase cGMP levels.
Acetylcholine's actions are mediated via a number of mechanisms which are not all
cAMP or gAMP-dependent. These include increasing intracellular concentrations of
inositol 1,4,5-triphosphate (ITP) and diacylglycerol (DAG) as well as promoting Ca
influx through L-type Ca channels. The ITP effects are thought to be responsible for
the initial phase of bronchial smooth muscle contraction, mediated via a transient
increase in intracellular calcium concentration through release from the
sarcoplasmic reticulum. Despite this apparent cAMP-independence, it has been
postulated that it may be a cholinergic mediated decrease in cAMP which is the
cause of the increased intracellular ITP concentration.
Although this first phase may be AMP-independent, both ITP and DAG levels appear
to be involved in the maintenance of contraction via modification of cAMP levels
through unknown mechanisms.
As mentioned above adrenergic stimulation can result in both α1-adrenoreceptor
mediated bronchial constriction, α2-adrenoreceptor mediated bronchodilation
probably through inhibition of cholinergic bronchoconstriction 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 trans-membrane
potential and hence a reduction in Ca influx through the voltage-dependent L-type Ca
channels, thereby resulting in bronchodilation.
Consequently bronchodilation may be achieved via anticholinergic agents
(including α2agonists), β2 adrenergic receptor agonists and agents such as the
methylxanthines which produce bronchodilation at least in part due to increased
intracellular cAMP levels in bronchial smooth muscle.
Clinical Indications

The use of bronchodilators in various disease states is based on the assumption

that clinically significant bronchoconstriction exists. Although this has been shown
in a small proportion of dogs with inflammatory bronchopulmonary disease, it is in
cats where bronchoconstriction is a frequent feature of inflammatory bronchial
disease. As the signs of bronchoconstriction can dominate the clinical syndrome,
feline inflammatory airway disease is frequently referred to as "feline asthma" as it is
thought to resemble the human syndrome of the same name.
It is worth noting that in the cat, as in man, "asthma" can no longer be thought of
simply as reversible airway obstruction or "irritable airways". Current information
suggests "asthma" should be viewed as an inflammatory disease that has bronchial
hyperreactivity and bronchospasm as one of its consequences. Although some
affected individuals will have an allergic basis to this inflammatory process others
will not.
Asthmatic inflammation is initiated by the release of an enormous variety of
inflammatory mediators, each having more than one effect on airway inflammation.
The resultant vasodilation, and increased vasopermeability produces an influx into
the bronchial tissues of inflammatory cells which then release their own mediators
with their own inflammatory effects. The chronic results are airway edema, smooth
muscle hypertrophy, epithelial shedding and bronchial hyperreactivity to non-specific
stimuli.
The complexity of this inflammatory process, driven by multiple mediators of
inflammation with each mediator having numerous effects, would suggest that a
drug affecting one mediator is unlikely to have substantial benefit, simply because
there are so many mediators participating in the process. In addition, it seems likely
that drugs which broadly address asthmatic inflammation are likely to be of more
therapeutic benefit than agents that are basically modifiers of bronchoconstriction.
In man, recent clinical trials comparing the benefits of anti-inflammatory treatment
with those of bronchodilator therapy in asthmatics have shown the usefulness of
addressing the inflammatory process as the underlying problem, rather than
attempting to correct some of the more dramatic clinical consequences of asthmatic
inflammation.
Nevertheless symptomatic bronchodilator therapy remains a therapeutic option
and certainly may have substantial benefit in some cases.
The following sections will concentrate on specific bronchodilators as well as the
use of leukotriene-receptor antagonists, a group of drugs that can potentially modify
a number of the mediators of asthmatic inflammation.
Adrenergic Agonists

All adrenergic agonists have variable α and β receptor affinity. In view of the
distribution of α and β receptors, non-selective β receptor agonists such as
isoprenaline or mixed α and β receptor agonists such as adrenaline 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.
A possible exception may be with the treatment of acute allergic bronchospasm. In
this situation, the α2receptor-mediated inhibition of cholinergic bronchospasm may
be helpful. For this reason, the use of an adrenergic agent with both β2 and α2 agonist
activity may be beneficial in the peracute management of allergic bronchospasm.
However, in view of the risks associated with administering systemic non-selective
adrenergic agonists to a potentially hypoxic and already tachycardic patient, it is
clearly preferable for them to be administered by inhalation rather than systemically.
Even when selective β2 agonists are used, the preferential 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 systemic drug concentrations.
Aerosol administration relies upon the delivery of drug distal airways which in turn
depends on the size of the aerosol particles and various respiratory parameters such
as tidal volume and inspiratory flow rate. Even in such a cooperative patient as man
only approximately 10% of the inhaled dose enters the lungs. Effective aerosol
therapy is possible for dogs and cats especially for short periods or in emergency
situations. However the general inconvenience of long-term bronchodilator therapy
raises significant compliance issues.
Although there are a large number of selective β2 receptor agonists commercially
available for use in man, most are presented in various inhalant preparations which
generally are unsuitable for regular use in small animals. The two principal ß2
agonists currently marketed in preparations that can be readily and regularly used in
small animals are terbutaline sulphate and albuterol sulphate.
Terbutaline sulphate: Terbutaline is a selective β2 receptor agonist which produces
relaxation of smooth muscle found principally in bronchial, vascular and uterine
tissues. Terbutaline is available as tablets, elixir and an injectable preparation
suitable for subcutaneous use. The dose rate has been reported from as low as 0.1-
0.2mg/kg/8h for the dog and cat given either orally or subcutaneously to as high as
1mg/kg/8h for an oral dose in the dog.
Albuterol sulphate: Albuterol is a selective β2 receptor agonist with
pharmacological properties similar to terbutaline. Albuterol is available as tablets
and syrup as well as various inhalants. The dose rate in the dog is 0.02mg/kg/12h.
This dose should be maintained for 5 days and if there has been no improvement nor
any adverse effects the dose may be increased to 0.5mg/kg/8-12h. In animals that
respond at this higher dose the dose should be reduced until the lowest effective
dose has been determined for each patient.
Recent studies have confirmed albuterol and prednisolone act synergistically in
producing bronchodilation in response to a standard bronchoconstricting stimulus.
Consequently concurrent glucocorticoid therapy may be worth considering in
patients proving refractory to albuterol's bronchodilatory effects. This may be given
either as oral preparations or topically (see below).
Topical bronchodilator therapy can be achieved effectively in cats using a standard
pediatric spacer equipped with a cat face mask on the 'patient' end. Most clinicians
recommend using both a B-blocker (such as albuterol) and topical glucocorticoids
such as fluticasone. The dose of albuterol is two 'puffs' from a generic inhaler and is
combined with a standard dose of inhaled fluticasone of 220ugm. Both are vaporised
in the spacer, the face mask placed over the cat's face and it is allowed to breath
through the mask for 7-10 seconds.
The inhalation procedure is usually given every 12 hours and is started in addition
to oral prednisolone if the cat is symptomatic at the time. Usually the prednisolone
can be stopped after 5-10 days and the inhalation continued for at least a further
month. Assuming adequate control, the dose of fluticasone can then be reduced to
110mgm every 12 hoursfor another month and then stop. Whether or not the
albuterol is required throughout this period is debatable. Some clinicians do not use
albuterol except at times when cats are symptomatic.
Methylxanthines

The methylxanthines share several pharmacological actions of therapeutic interest.

They relax smooth muscle, particularly bronchial smooth muscle, stimulate the
central nervous system, are weakly positive chronotropes and inotropes as well as
being mild diuretics. However it is as bronchodilators that they have been most
widely used in small animal veterinary practice.
Theophylline and aminophylline: Caffeine, theophylline and theobromine are three
naturally occurring methylated xanthines. All three are relatively insoluble and this
solubility can be enhanced by the formation of complexes with a wide variety of
compounds. The best known of these complexes is aminophylline which is the
ethylenediamine complex of theophylline with differing quantities of water of
hydration. 100mg of hydrous and anhydrous aminophylline respectively contains 79
and 86 mg of anhydrous theophylline. Conversely, 100mg of anhydrous theophylline
is equivalent to 116mg of anhydrous aminophylline and 127mg of hydrous
aminophylline. When dissolved in water, aminophylline readily dissociates to its
parent compounds.
 The pharmacokinetics of theophylline has been extensively studied in a number of
species. After oral administration rate of absorption is limited principally by
dissolution of the dosage form in the gut. Bioavailability in both cats and dogs is
generally 100% when non-sustained release preparations are used. However
sustained release preparations may have a more variable bioavailability. One study in
dogs suggested four different sustained release preparations has bioavailabilities
varying from 30-76% however other investigators found bioavailability to be greater
than 95% in studies using two of these four products.
Theophylline is only weakly protein bound (7-14%) with a relatively low volume of
distribution (0.82 L/kg, dogs; 0.46 L/kg, 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.
Because of theophylline's relatively low therapeutic index and pharmacokinetic
characteristics, dose rates should be determined on lean body mass. Dose
conversions between aminophylline and theophylline can be determined from the
information present in the chemical structure section.
The dose rate of theophylline varies depending on the preparation used. In standard
preparations the recommended dose rate in dogs is 10mg/kg/6-8h and cats
4mg/kg/8-12h. When using the sustained release preparations a dose of
20mg/kg/12h for dogs and 25mg/kg/24h for cats should be considered. Although
there have been reports of varied bioavailability with different proprietary forms of
sustained release preparations, Theo-Durr and Diffumal have both been shown to
reliably have bioavailability greater than 95% in dogs.
The dose rate of aminophylline is 11mg/kg/8h in dogs and 5-6mg/kg/12h in cats.
Antitussives
Relevant Pathophysiology

The cough reflex is complex, involving the central and peripheral nervous system as
well as the smooth muscle of the bronchial tree. It has been suggested that irritation
of the bronchial mucosa causes bronchoconstriction, which in turn stimulates
cough receptors located within the tracheo-bronchial tree. Afferent conduction from
these receptors is via the vagus too possibly multiple centres within the medulla that
are distinct from the actual respiratory centre. The drugs that can affect this
complex mechanism are quite diverse. For example when coughing as a result of
bronchoconstriction may be relieved by bronchodilators acting simply to dilate
airways while other antitussive agents might act primarily on the peripheral or
central nervous system components of the cough reflex. Generally however the
most effective antitussives have been shown to elevate the threshold for coughing
by poorly understood centrally mediated mechanisms.
Clinical Indications

Almost all respiratory tract disorders involving the large and small airways result in
coughing. Frequently this can be viewed as a protective physiological process
resulting in clearing of viscoid secretions produced by chronic airway inflammation.
As prolonged contact between inflammatory mediators in the mucus and epithelial
cells perpetuates inflammation any form of cough suppression needs to be
instituted cautiously. However once clinical signs suggest the coughing is resolving,
cough suppression may be desirable as chronic coughing tends to increase airway
inflammation, increasing the risk of a vicious cycle of cough leading to mucosal
irritation which creates further coughing. Additionally, chronic coughing for any
reason will increase the risk of irreversible emphysema. Consequently cough-
suppression may be particularly helpful in certain situations. Perhaps the most
common condition where cough suppression plays an integral part in successful
management is dynamic airway disease.
Typically drugs used to suppress coughing are categorized as opioid or non-opioid
antitussive agents. Unfortunately, although most of the non-opioid antitussives are
effective against coughing induced by various experimental techniques, the ability of
these tests to predict clinical efficacy is limited. Consequently in different patients,
therapeutic trials with various antitussives may be required in order to achieve
effective cough suppression.
Non-opioid Antitussives

Dextromethorphan hydrobromide: Dextromethorphan hydrobromide is a synthetic

cough suppressant which 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 nor inhibit ciliary activity. Dextromethorphan binds to central
binding sites that appear to be distinct from standard opioid receptors. The non-
opioid nature of these sites is reinforced by the inability of naloxone to reverse
dextromethorphan's effects.
Dextromethorphan is generally marketed in "over the counter" formulations usually
syrups or lozenges) combined with various antihistamines, bronchodilators and
mucolytics. A dose of approximately 2 mg/kg has been suggested although, as with
most of the antitussive agents, higher doses are often required. Antitussive effects
may persist for up to 5 hours. In the author's experience, dextromethorphan's efficacy
is significantly less than the various opioid antitussives. Its main advantage in most
situations is its ease of availability and convenience.
Diphenhydramine: Among other drugs which have been used as antitussives, the
antihistamine diphenhydramine is perhaps the most ubiquitous. Its antitussive
mechanism of action is unclear and controlled studies on its efficacy in dogs and
cats are not available. As diphenhydramine may produce drowsiness in
recommended doses its value as an antitussive in dogs and cats remains at best
debatable.
Opioid Antitussives

Codeine phosphate. Due to reduced first-pass hepatic metabolism codeine has a

high oral-parenteral potency for an opioid with oral administration of codeine
providing 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 man approximately 10% of administered codeine is demethylated to
form morphine and both fee and conjugated forms of morphine can be found in the
urine of patients receiving therapeutic doses of codeine. In man, codeine's plasma
half-life is around 2 to 4 hours.
Codeine phosphate is contained in numerous "over the counter" analgesic
preparations as well as in 30 and 60mg tablets which have restricted scheduling. The
starting antitussive dose has been as low as 0.1-0.3mg/kg/8-12h and as high as 1-
2mg/kg/6-12h. Whatever the starting point, the dose may need to be increased to
achieve a satisfactory effect.
 Hydrocodone tartrate: Hydrocodone exhibits the properties of other opiate
agonists however has reportedly increased antitussive properties compared to
codeine. The mechanism of this effect seems to be direct suppression of the cough
centre within the medulla. It has been suggested that hydrocodone may also reduce
respiratory mucosal secretions through undetermined mechanisms.
In dogs the antitussive effect generally lasts between 6-12 hours.
The dose rate in dogs is 0.25mg/kg/6-12h. Hydrocodone is only marketed in
combination with homatropine as both an elixir and tablet formulations. The addition
of homatropine is designed to enhance any reduction in respiratory secretions, which
may come about as a result of the administration of hydrocodone.
Dihydrocodeine tartrate: Hydrocodeine also acts centrally to raise the cough
threshold. Its other CNS activities seem to be markedly less than codeine.
Dihydrocodeine is marketed as an elixir, which is relatively palatable and well
absorbed. A starting dose rate of 2mg/kg/8-12h is recommended although higher
doses may be required for satisfactory therapeutic effect.
Butorphanol: Butorphanol is an effective antitussive as well as analgesic. In dogs it
has been shown to elevate CNS respiratory centre threshold to pCO2 but unlike other
opioid agonists it does not suppress respiratory centre sensitivity. Butorphanol is well
absorbed orally however a significant first-pass effect results in less than 20%
appearing in the systemic circulation. It is well distributed and in man approximately
80% protein bound.
The antitussive dose of butorphanol in dogs is 0.55-1.1mg/kg/6-12h orally or
0.055-0.11mg/kg/6-12h subcutaneously.
Diphenoxylate: General pharmacokinetics and pharmacodynamics: Diphenoxylate
is an opioid agonist traditionally thought of exclusively as an antidiarrheal agent.
However it also has effective antitussive activity, presumably through direct
suppression of the cough center. In most countries it is only available in combination
with atropine as an anti-diarrheal agent. In dogs, diphenoxylate can be used in this
combination as an effective antitussive with minimal side effects. The dose rate is
approximately 0.25mg/kg8-12h orally.
Mucolytics
Relevant Pathophysiology

The viscosity of pulmonary mucus secretions depends on the concentrations of

mucoproteins and deoxyribonucleic acid (DNA). While mucoprotein is the main
determinant of viscosity in normal mucus, in purulent inflammation the mucoid
concentration of DNA increases (due to increased cellular debris) and so does its
contribution to mucoid viscosity.
Clinical Indications

In a proportion of patients with respiratory tract disease, significant bronchial

inflammation will be associated with the presence of large amounts of relatively
viscous, inflammatory exudate and mucus which is firmly attached to the lining of
bronchioles and bronchii. By effectively increasing bronchial wall thickness, this
thick adherent mucus can exacerbate the "lumen-narrowing" effects of bronchial
constriction, enhance the overall inflammatory process as well potentiating
persistent coughing. In this situation mucolytic therapy may have some value in
facilitating resolution of the inflammatory airway disease.
 The two most frequently prescribed mucolytics in veterinary practice are described
below. In man, guaifenesin has been proposed as an oral expectorant or mucolytic.
However, evidence for its efficacy in this role is lacking in animals and currently its
use in veterinary practice is confined to its significant muscle relaxant activity. It is
also worth remembering that normal saline, directly administered to the airways by
effective nebulisation therapy, is an extremely effective mucolytic and expectorant.
Bromhexine Hydrochloride

Bromhexine increases mucus viscosity by increasing lysosomal activity. This

increased lysosomal activity enhances hydrolysis of acid mucopolysaccharide
polymers, 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 fibres present. As bromhexine does
not effect these DNA fibres, its mucolytic action is limited in these situations.
It has also been suggested that bromhexine increases the permeability of the
alveolar/capillary barrier resulting in increased concentrations of certain antibiotics
in luminal secretions. Furthermore over time (2-3days) bromhexine results in a
significant increase in γ-globulin concentrations and a decline in albumin and γ-
globulin concentrations in respiratory secretions. The increased g-globulins are IgA
and IgG while IgM levels remain unchanged. It has been hypothesized that because
of these effects concurrent administration of bromhexine and an antimicrobial agent
will facilitate treatment of infectious tracheobronchitis.
The mucolytic dose of bromhexine hydrochloride in dogs and cats is 2mg/kg/12h
orally for 7 to 10 days then 1mg/kg/12h for a further 7-10 days.
Acetylcysteine

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
sulphydryl group on acetylcysteine reducing the disulphide 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 increase with increasing pH.
For effective mucolytic activity, an acetylcysteine solution should be nebulised and
administered directly to the respiratory mucosa as an aerosol. The dose rate in dogs
and cats is 50ml/kg for 30 minutes every 12 hours.
Acetylcysteine is available as 10% and 20% solutions of the sodium salt in various
sized vials. This solution can be readily used in a nebuliser undiluted although
dilution with sterile saline will reduce the risk of reactive bronchospasm.
Speaker Information

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

David Church

Department of Veterinary Clinical Science

The Royal Veterinary College

North Mymms, Hertfordshire, United Kingdom

URL: https://www.vin.com/doc/?id=3858955