Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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 somewhat
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 inflammatory
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 situation,
mucolytic therapy has theoretical value in facilitating
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 remembering
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 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 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, resulting
in increased concentrations of certain antibiotics
in luminal secretions. Furthermore, over time (2–3 d),
bromhexine results in a significant increase in immunoglobulin
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 bromhexine
and an antimicrobial agent will facilitate treatment
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, undergoes
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 nebulizer
undiluted, although dilution with sterile saline will reduce the risk
of reactive bronchospasm.
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