Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTILEUKOTRIENES
Pharmacokinetics
When given orally, acetylcysteine is well absorbed; when
given by nebulization directly into the respiratory tract,
most acetylcysteine is involved in the sulfhydryldisulfide
reaction and the remainder is absorbed. The
absorbed drug is metabolized via deacetylation to cysteine
in the liver.
Adverse effects
Unfortunately, acetylcysteine appears to irritate respiratory
tract epithelium and many dogs and cats develop
cough and/or bronchoconstriction when acetylcysteine
is administered directly into the respiratory tract. Consequently,
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 documented
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 guaifenisin.
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 commonly
prescribed. Thus, at doses recommended to treat
humans with COPD the effect of guaifenisin is likely
equivalent to placebo.
ANTILEUKOTRIENES
Clinical applications
Leukotrienes belong to a family of inflammatory mediators
that are derived from arachidonic acid and are
known collectively as eicosanoids. Arachidonic acid is
metabolized to various prostaglandins and thromboxanes
through the action of cyclo-oxygenase as well as
various leukotrienes through the action of the lipoxygenase
system.
The 5-lipoxygenase enzyme catalyzes the conversion
of arachidonic acid to 5-hydroperoxy-eicosatetraenoic
acid (5-HPETE) and then to leukotriene A4 (LTA 4 ).
LTA 4 is then converted to LTB 4 or conjugated to LTC 4 .
LTC 4 is converted to LTD 4 and this is metabolized to
LTE 4 . The leukotrienes LTC 4 , LTD 4 and LTE 4 are collectively
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, particularly
eosinophils and neutrophils.
The cysteinyl leukotrienes act via two types of cell
surface receptor: cys-LT 1 and cys-LT 2 . While the cys-LT 2
receptor is mainly responsible for the effects of cysteinyl
leukotrienes on pulmonary blood vessels, cys-LT 1 receptors
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
LTC 4 , LTD 4 and LTE 4 . Specifically, zileuton blocks leukotriene
biosynthesis by inhibiting production of the
5-lipoxygenase enzyme while both montelukast and zafirlukast
block adhesion of leukotrienes to their common
leukotriene receptor (cys-LT 1 ).
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 administration
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. LTE 4 is found in increased concentrations in
urine of asthmatic humans and is a commonly used
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