Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 22 DRUGS USED IN THE TREATMENT OF ADRENAL DYSFUNCTION
antifungal therapy). However, at doses higher than
those recommended for antifungal activity, ketoconazole
can inhibit steroid synthesis.
Ketoconazole is an effective inhibitor of adrenal and
gonadol steroidogenesis primarily as a result of its
inhibition of the 17-hydroxylation activity of P450 17α .
In other words, ketoconazole inhibits the conversion of
progesterone and pregnenolone to 17α-hydroxyprogesterone
and 17α-hydroxypregnenolone. At higher doses,
ketoconazole also inhibits P450 scc , effectively blocking
steroidogenesis in all primary steroidogenic tissues (see
Fig. 22.1).
Formulations and dose rates
For the treatment of hyperadrenocorticism a dose of 15 mg/kg/12 h
is generally recommended. Most authors suggest starting at a dose
of 5 mg/kg/12 h for 7 d and if no adverse effects are noticed, increasing
the dose to 10 mg/kg/12 h for 14 d and evaluating adrenal suppression
with an ACTH stimulation test at the end of this period.
Although a small number of cases will be ‘adequately suppressed’ (in
the author’s opinion, defi ned as a post-ACTH cortisol within the
laboratory’s normal range for basal cortisol) with this dose, most
require 15 mg/kg/12 h.
Ketoconazole is more effectively absorbed in an acidic environment.
Although the manufacturer recommends dosing with food to
reduce the risk of GIT side effects, unfortunately, this is likely to
reduce bioavailability.
The disadvantages of ketoconazole include its lack of effi cacy in a
high proportion of cases (reportedly ineffective in 25–50% of cases),
the need for constant twice-daily dosing and in many countries its
expense.
Pharmacokinetics
In the dog, oral bioavailability appears to be quite variable,
with one report suggesting a range of 4–89% and
peak serum concentrations in the range 1.1–45.6 µg/
mL. Ketoconazole’s absorption is enhanced in an acidic
environment, however, and absorption may be facilitated
by dosing after fasting. Ketoconazole is approximately
90% protein bound, undergoes extensive hepatic
metabolism and these inactive metabolites are predominantly
excreted in the feces via the bile.
Adverse effects
● Gastrointestinal effects including anorexia, vomiting
and diarrhea are the most common adverse effects of
ketoconazole administration. Although dividing the
dose or dosing with food may reduce anorexia, the
latter may reduce absorption.
● Hepatotoxicity has been reported in both dogs and
cats and may be idiosyncratic or dose related.
● Thrombocytopenia is a rare adverse effect.
● There have been rare reports of changes in hair coat
color in animals.
Known drug interactions
● Antacids, anticholinergics and H 2 -blockers all
increase gastric pH and may inhibit absorption of
ketoconazole.
● Any agent that may produce adrenocorticolysis or
inhibit steroidogenesis is likely to potentiate ketoconazole’s
inhibition of adrenal and gonadal
steroidogenesis.
● In contrast, ketoconazole alters the disposition and
extends the duration of activity of methylprednisolone
and possibly other synthetic glucocorticoids.
● Ketoconazole may increase plasma concentrations of
cisapride (with a resultant increased risk of ventricular
arrhythmias).
● Ketoconazole may increase plasma concentrations of
ciclosporin.
● Ketoconazole may decrease plasma concentrations of
theophylline.
● Phenytoin and ketoconazole modify each other’s
metabolism.
● As ketoconazole is hepatotoxic it should not be
administered with other hepatotoxic agents.
Mitotane
Mechanism of action
Mitotane is the o,p′ isomer of DDD which is structurally
related to chlorophenothane (DDT). By binding to and
destroying mitochondria, mitotane’s active metabolite
exerts a direct cytotoxic effect on the adrenal cortex,
resulting in relatively selective progressive necrosis of
the zona reticularis and fasciculata. Mitotane also interferes
with adrenal steroidogenesis by poorly understood
mechanisms although inhibition of 11β-hydroxylase is
likely to be involved.
Formulations and dose rates
Although there are numerous reports on how mitotane should be
administered to dogs with PDH, many involve small variations around
two basically different strategies. Both protocols involve creating profound
adrenocorticolysis. However, in one the aim is to leave suffi cient
adrenocortical activity for normal day-to-day activities while the
second attempts to achieve complete ‘chemical adrenalectomy’ and
provide long-term glucocorticoid and mineralocorticoid supplementation
as required.
Protocol 1
This protocol has two basic parts: a remission-inducing sequence and
a remission-maintaining sequence.
Remission induction: The aim of this part of the treatment
protocol is to create marked adrenocorticolysis resulting in an inability
of the remaining adrenal tissue to mount any response to supraphysiological
doses of ACTH. Additionally, most endocrinologists suggest
an improved clinical response is achieved if both the basal and post-
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