Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 22 DRUGS USED IN THE TREATMENT OF ADRENAL DYSFUNCTION
Formulations and dose rates
The use of cyproheptadine for the control of PDH has not been extensively
evaluated. However, in one of the few reports of its effi cacy,
doses of 0.3–3.0 mg/kg/24 h produced only variable clinical and biochemical
responses in less than 10% of dogs with PDH.
Pharmacokinetics
The pharmacokinetics of cyproheptadine suggest it is
well absorbed orally, undergoes extensive hepatic
metabolism and that metabolites are predominantly
renally excreted.
Adverse effects
At usual doses the most commonly reported adverse
effects have been sedation, anticholinergic effects and
polyphagia.
Known drug interactions
● Cyproheptadine may enhance CNS depression
when used with sedatives.
● Monoamine oxidase inhibitors such as deprenyl may
intensify cyproheptadine’s anticholinergic effects.
Bromocriptine
Bromocriptine is also discussed in Chapter 7 (Behaviormodifying
drugs).
Mechanism of action
Bromocriptine is an ergot-derived alkaloid with dopaminergic
activity. It is a strong D 2 -receptor agonist and
a partial D 1 -receptor agonist. These are the two major
dopamine receptors found within the striatum of the
CNS in humans and are presumed to be most important
in the treatment of Parkinson’s disease.
As a result of this dopamine receptor agonist activity,
it has been postulated that bromocriptine may have
some potential to lower ACTH secretion, particularly
in PDH patients in which increased ACTH secretion
may be a result of reduced dopaminergic activity at the
pars intermedia.
It should be remembered that dopamine is an effective
inhibitor of prolactin secretion from the anterior pituitary.
This appears to be achieved either by a direct
effect on the pituitary or by stimulation of postsynaptic
dopamine receptors in the hypothalamus, resulting in
release of prolactin-inhibitory factor.
Formulations and dose rates
Bromocriptine has been evaluated in the treatment of PDH in dogs
with doses ranging from 0.01 to 0.1mg/kg/24 h either as a single
dose or divided. Regardless of the dose, the effi cacy has been low
and the adverse effects frequent.
Pharmacokinetics
The pharmacokinetics of bromocriptine in dogs and
cats have not been described. In humans approximately
30% of orally administered bromocriptine is absorbed
and only 6% is available due to a significant first-pass
effect. In humans the drug is highly protein bound,
undergoes extensive hepatic metabolism with a half-life
of 3–7 h.
Adverse effects
● Adverse effects are common with bromocriptine and
generally are dose related.
● Most frequently encountered problems include
anorexia, vomiting, diarrhea, generalized weakness
and depression as well as hypotension.
● Rarely, profound hypotension may occur after the
first dose. For this reason bromocriptine should be
started at a low dose and with gradual increments
after regular monitoring.
● Generally, the frequency with which adverse effects
are encountered has limited the use of bromocriptine
for the treatment of PDH.
Known drug interactions
The hypotensive effects of bromocriptine may be additive
when used in conjunction with other hypotensive
agents.
Selegiline (L-deprenyl)
Selegiline is also discussed in Chapter 7 (Behaviormodifying
drugs).
Mechanism of action
Selegiline is 2-proponylphenethylamine, an irreversible
inhibitor of MAO-B. It is a specific inhibitor of MAO-B,
the enzyme that is predominantly responsible for
catalyzing the metabolism of CNS dopamine.
In the dog, CRH stimulates release of ACTH from
the pars distalis while local dopamine levels tonically
inhibit ACTH secretion from the pars intermedia. As
MAO activity reportedly increases with age, it has been
suggested that at least in some cases, PDH in the dog
may be a result of dopamine depletion.
By inactivating MAO-B, selegiline may increase
CNS dopamine levels and decrease pars intermedia
derived-ACTH.
Additionally, it has been suggested dopamine depletion
may increase CRH-stimulated ACTH secretion
from the pars distalis, providing a further possible
means by which selegiline may reduce ACTH secretion
in PDH patients.
518