Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 22 DRUGS USED IN THE TREATMENT OF ADRENAL DYSFUNCTION
hydrocortisone by a distinct 11β-hydroxysteroid dehydrogenase
operating in a reductive mode.
As cortisone is rapidly 11-hydroxylated to cortisol, it
provides a complete replacement for any form of cortisol
deficiency. As it has equipotent glucocorticoid and
mineralocorticoid activity, it will also provide more
mineralocorticoid activity than other synthetic glucocorticoids
such as prednisolone. In addition, its shorter
half-life and lower overall activity means it is less likely
to create iatrogenic hyperadrenocorticism with longterm
administration.
Formulations and dose rates
In patients with hypoadrenocorticism, orally administered cortisone
acetate can be used as an effective long-term cortisol replacement.
Depending on the country of origin, these can be supplied as 5 mg,
10 mg and 25 mg tablets. The dose in dogs is 0.5–1 mg/kg/12–24 h.
The dose must be individualized according to the severity of the condition,
the response obtained and what other glucocorticoid or mineralocorticoid
is being concurrently administered.
Pharmacokinetics
There is little information available regarding the pharmacokinetics
of cortisone in dogs. An early report suggested
cortisone had a half-life of 1 h in normal dogs.
A more recent study of eight dogs given approximately
1.25 mg/kg of cortisone acetate orally revealed rapid
absorption, a peak plasma cortisol concentration of
300–500 nmol/L occurring approximately 1 h after
dosing and plasma levels returning to baseline around
5 h after dosing. There was no effect of feeding on these
parameters. However, the reports suggested that spontaneous
hypoadrenocorticism delayed metabolism and/
or excretion of adrenosteroids.
Adverse effects
Adverse effects are uncommon and are usually dose
dependent.
9a-Fludrocortisone
Mechanism of action
9α-Fludrocortisone is synthetic adrenocortical steroid
with a fluoride ion substituted at the 9α position and
an 11β-hydroxyl group, giving it both glucocorticoid
and mineralocorticoid potency. Because of the 9α fluoride
substitution, 9α-fludrocortisone has potent mineralocorticoid
activity while the 11-hydroxylation confers
significant glucocorticoid activity. When compared to
hydrocortisone, 9α-fludrocortisone has 10 times the
glucocorticoid activity and 125 times the mineralocorticoid
activity.
Formulations and dose rates
The dose of 9α-fl udrocortisone is 10–30 µg/kg/24 h. Typically a
lower dose is used to start with and it may be titrated up on the basis
of clinical impression and plasma electrolyte concentrations. Dose
adjustments are usually made after weekly electrolyte evaluations.
Once they are stable and within the normal range, adjustments can
be made every 3–4 months.
In patients receiving concurrent long-term 9α-fl udrocortisone, it is
not uncommon for the dose of 9α-fl udrocortisone to increase over
time, as there appears to be a reduction in its mineralocorticoid effi -
cacy. In one study the daily maintenance dose increased from a
median of 13 µg/kg to a fi nal median dose of 23 µg/kg while the fi nal
dose of fl udrocortisone administered to more than half the dogs
ranged from 15 to 30 µg/kg/24 h. In another group of hypoadrenocorticoid
dogs treated with 9α-fl udrocortisone and considered well
controlled clinically, 84% had hyponatremia, hyperkalemia and/or a
subnormal sodium:potassium ratio. Unfortunately, titrating up the 9αfl
udrocortisone dose in an attempt to normalize plasma electrolyte
levels can result in excess glucocorticoid activity and dogs can
develop signs of iatrogenic hyperadrenocorticism while still not having
normal sodium and potassium levels. Reasons for this ‘9α-fl udrocortisone
creep’ are not clear although poor compliance may play a role,
as might tachyphylaxis.
A substantial proportion of patients receiving 9α-fl udrocortisone do
not require maintenance glucocorticoid supplementation after initial
stabilization. In patients that do require glucocorticoids, cortisone
acetate is the preferred choice in small dogs and cats to minimize the
risk of overdosing. In these patients the 9α-fl udrocortisone dose
required to maintain normal electrolyte levels is generally at the lower
end of the suggested dose range.
Pharmacokinetics
In humans 9α-fludrocortisone is well absorbed from the
gastrointestinal tract with peak levels occurring approximately
1.7 h after dosing. Like most steroids (which, of
course, act intracellularly) although the plasma half-life
of 9α-fludrocortisone is 3–5 h, biological activity persists
for 18–36 h.
Adverse effects
Adverse effects of 9α-fludrocortisone are generally associated
with overdosing or sudden withdrawal.
Known drug interactions
Patients may develop hypokalemia if 9α-fludrocortisone
is administered concurrently with amphotericin B or
potassium-depleting diuretics such as thiazides and
furosemide. In addition, it should be used cautiously in
patients receiving digoxin.
Deoxycorticosterone pivalate
Mechanism of action
Deoxycorticosterone pivalate (DOCP) is a long-acting
mineralocorticoid (see Fig. 22.1). As it has neither an
11β- nor a 17α-hydroxylation, theoretically it has little
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