Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS ACTING ON THE ADRENAL CORTEX
stimulation plasma cortisol concentrations remain within the bottom
third of the normal range for basal plasma cortisol.
Specifi cally this goal is achieved by the oral administration of
mitotane with a meal at a dose of 25 mg/kg/12 h for 5–7 d. At the
end of this period an ACTH response test is performed not less than
36 h after the last mitotane dose. This timing recommendation is to
insure the ACTH response test is evaluating the adrenocorticolytic
effect of mitotane and not its inhibitory effects on steroidogenesis. If
both basal and post-ACTH cortisol values are in the desired range,
the treatment moves to the remission-maintaining stage; if not, the
remission induction process is repeated.
Generally, satisfactory adrenocorticolysis is achieved with total
mitotane doses of 250–700 mg. Furthermore, the total dose required
for remission induction is usually an indication of the weekly dose
required for remission maintenance.
As there is potential for either absolute or relative iatrogenic hypoadrenocorticism,
it is prudent to provide owners with an oral glucocorticoid
like prednisolone. This can then be used when there are
suspected signs of hypoadrenocorticism or any acute non-adrenal
illness. These are potentially critical situations in patients undergoing
remission induction and administering prednisolone while awaiting
veterinary attention substantially reduces the risk of a life-threatening
problem developing.
Remission maintenance: Once satisfactory adrenocorticolysis
has been achieved, remission is maintained by the weekly oral
administration of mitotane at a dose of 30–100 mg/kg/week. Generally
this is administered in two doses, each with a meal, on one day
per week. Maintenance of remission is evaluated by regular ACTH
stimulation tests or possibly urinary corticoid:creatinine ratios.
Protocol 2
Mitotane is administered at a dose of 50–75 mg/kg/24 h for 25 d. The
dose is usually divided into three or four and given with food. Owners
are instructed to stop mitotane administration if the dog becomes
inappetent and to resume administration once it returns (generally in
2–3 d). When severe side effects are seen the mitotane dose should
be reduced and/or the daily dose further subdivided.
On the third day, glucocorticoid and mineralocorticoid replacement
is started. This consists of cortisone acetate at a dose of 1 mg/
kg/12 h together with 9α-fl udrocortisone at 7 µg/kg/12 h and sodium
chloride supplementation at 50 µg/kg/12 h. All owners are given
injectable glucocorticoid and mineralocorticoid supplements to be
used if more than two successive oral replacement treatments are
missed.
Effective complete chemical adrenalectomy is confi rmed with an
ACTH stimulation test 30 d after mitotane administration was begun
and at this time the dose of cortisone is reduced to 0.5–1.0 mg/
kg/24 h. Animals should be re-evaluated every 6 months or sooner if
the owners suspect a relapse. Doses of 9α-fl udrocortisone and NaCl
are adjusted on the basis of plasma electrolytes while the cortisone
acetate dose is reduced or stopped if there are any signs of
hyperadrenocorticism.
With this protocol approximately 40% of dogs relapse and require
further 25-d induction protocols.
Interestingly, in one large study of mitotane therapy in canine PDH,
bigger dogs remained disease free for signifi cantly longer than small
dogs. This may indicate that small dogs require a higher dose of
mitotane or a dose based on surface area. However, to date neither
possibility has been evaluated.
Pharmacokinetics
The bioavailability of mitotane is poor, although this
may be enhanced by administering the drug with food.
Interestingly, mitotane’s bioavailability appears to be
higher in dogs with PDH. In dogs, peak plasma concentrations
occur approximately 4 h after dosing with an
elimination half-life after a single dose of 1–2 h. The
rapidity of this calculated elimination time is somewhat
misleading, however. Elimination from plasma will be
prolonged after chronic dosing as the drug is slowly
released from adipose tissue where it is present in high
concentrations. This same phenomenon is present in
humans, where plasma half-lives ranging from 18 to
159 d have been reported.
In humans, mitotane is predominantly metabolized by
the liver and this is also likely to be the case in dogs.
Consequently, any drug which enhances the hepatic
microsomal system is likely to accelerate mitotane’s
metabolism. Additionally, mitotane may facilitate its
own metabolism by activation of the hepatic microsomal
enzyme system.
Adverse effects
● Adverse effects are relatively common in dogs receiving
mitotane. Although many of these are due to
acute glucocorticoid deficiency, mitotane itself can be
associated with various gastrointestinal disturbances,
behavioral changes, cranial nerve palsies and transient
muscle weakness.
● In a small proportion of cases receiving mitotane,
severe and irreversible glucocorticoid and mineralocorticoid
deficiency will develop. This appears to be
an idiosyncratic reaction and occurs independent of
dose, age or severity of hyperadrenocorticism.
Known drug interactions
● As mitotane can induce hepatic microsomal enzymes,
it may enhance the metabolism of a number of different
drugs such as the barbiturates and warfarin.
● Mitotane also has its metabolism enhanced by the
barbiturates; consequently animals on barbiturates
will require higher doses of mitotane.
● Spironolactone has been shown to block the effects
of mitotane.
● Diabetic patients may have their insulin requirement
lowered by mitotane administration.
Metyrapone
Mechanism of action
Metyrapone or metopirone is 2-methyl-1,2-di-3-pyridl-
1-propanone. It reversibly inhibits the synthesis of cortisol,
cortisone and aldosterone by blocking enzymatic
11β-hydroxylation. The reduction in cortisol synthesis
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