Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

METHYLXANTHINES
dilatory effects for up to 8 h. Anecdotal experience with
this drug in clinical practice suggests a similar pharmacokinetic
profile in cats. Salbutamol undergoes extensive
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 generally
subside after 2–3 days.
● As with terbutaline, care should be exercised when
administering salbutamol to patients with preexisting
cardiac disease, diabetes mellitus, hyperthyroidism,
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 chronotropes
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 complexes
is aminophylline, which is the ethylenediamine
complex of theophylline with differing quantities of
water of hydration. Each 100 mg of hydrous and anhydrous
aminophylline contains 79 mg and 86 mg of
theophylline respectively. Conversely, 100 mg of theophylline
is equivalent to 116 mg of anhydrous aminophylline
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
has also been credited with producing centrally mediated
increased respiratory effort at any given alveolar
PCO 2 , improved diaphragmatic contractility and
reduced diaphragmatic fatigue, mild increases in myocardial
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 inhibition
of phosphodiesterases with a resultant increase in
intracellular cAMP, direct and indirect effects on intracellular
calcium concentration, uncoupling of intracellular
calcium concentration and muscle contractile
elements and competitive inhibition of adenosine
receptors.
Interestingly, at therapeutic concentrations of theophylline,
only adenosine receptor blockade has been
reliably demonstrated. Consequently many investigators
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 pharmacokinetic
characteristics, dose rates should be based on lean body
mass. The dose rate of theophylline varies depending on the preparation
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 extensively
studied in a number of species. Because theophylline
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 dissolution
of the dosage form in the gut. Bioavailability in
both cats and dogs is generally >90% when nonsustained-release
preparations are used. However, sustained-release
preparations may have a more variable
bioavailability. One study in dogs suggested that
four different sustained-release preparations had bioavailability
varying from 30% to 76%; however, other
investigators found bioavailability to be greater than
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