The pathways for the synthesis of cortisol (and the effects of several drugs on the pathway) is shown here:
Pituitary-Dependent Hyperadrenocorticism (PDH)
Mitotane (Lysodren® , o,p'-DDD)
General Information:
This is the most commonly employed drug for treating PDH in the United States
The mode of action is direct, cytotoxic effects on the adrenal cortex. It's use results in the partial or complete destruction of the adrenal glands
Because it may destroy the adrenal glands' ability to produce even normal quantities of adrenocortical (glucocorticoids and mineralocorticoids) hormones, patients receiving it must be monitored with great vigilance for signs of adrenocortical deficieny...which can become a crisis, leading to shock then death! The importance of normal circulating levels of corticosteroids in the critical function of many organ systems has been discussed elsewhere and should be reviewed.
Treatment- Induction Phase:
The inital portion of the treatment plan is called the induction phase. During this time, lasting days....the drug is given and the owner and veterinarian monitor for the presence of clinical signs signaling the rapid fall in the level of circulating corticosteroids (cortisol).
inappetance
decreased water consumption
vomiting
diarrhea
lethargy
ataxia (weakness or vertigo)
A dose of 30-50 mg/kg per day is given with a fatty meal. It is acceptable to divide this daily dose. (Some clinicians also elect to give very low doses of prednisolone...0.15-0.25mg/kg/day...so that a rapid fall in circulating cortisol , and the resulting potential crisis from too little cortisol is mitigated by the presence of an exogenous corticosteroid. The problem here is that it becomes a little more difficult to recognize the clinical signs of a successful induction phase, or even whether a dose adjustment is in order to achieve a desirable low cortisol endpoint.)
The induction phase continues for 8-10 days, or isstopped if:
water comsumption decreases to 60ml/kg per day, or less
or decreased appetite /inappetance /anorexia develop IT IS ABSOLUTELY ESSENTIAL THAT PET OWNERS SPEAK WITH THE VETERINARIAN EVERY DAY, TO REPORT ON THE ATTITUDE, WATER CONSUMPTION AND APPETITE OF THEIR PETS. FAILURE TO STOP INDUCTION TREATMENT AT THE APPROPRIATE TIME CAN BE DEADLY!
if prednisolone was given during the induction phase, it should not be administered the day of the test (but can be resumed that day, after the test is completed).
goal is to see the basal (pre-ACTH) cortisol level in the normal basal range and the post-ACTH cortisol level in the same range as the basal level, or slightly above the basal range. (less than 4µg/dl)
if elevated basal or elevated post-ACTH cortisol levels are obtained, the induction phase is restarted, moving up to a higher dose, within the recommended dose range, and the above steps are repeated. Successful induction may take days, weeks or even months!
if the basal or post-ACTH cortisol levels are markedly depressed below the basal reference range, then mitotane is discontinued (no maintenance dose follows), prednisolone is continued, and the ACTH stimulation test is repeated at weekly intervals until the basal and post-ACTH cortisol levels are within the normal basal cortisol range.
Treatment- Maintenance Phase:
In general, once induction is successfully achieved, a weekly maintenance dose of about 50mg/kg...divided 2 or three days per week...is administered.
An ACTH Stimulation test is repeated at three and six months after beginning treatment, then at six month intervals.
The rationale for such frequent rechecks is because, on average, half the dogs on mitotane relapse by 12 months after beginning treatment. The testing is designed to catch these early, before full control is lost.
Side effects (vomit, diarrhea, lethargy) suggest that either the animal is intolerant of mitotane or circulating cortisol levels are too low; in the latter instance affected animals should receive supplemental prednisolone (0.2-0.5mg/kg) initially, then followed soon by an ACTH Stimulation test to assess the status of the adrenal cortex. Evaluation of mineralocorticoid function via examining serum sodium and potassium is also advised, particularly if side effects are not resolved via supplemental prednisolone. If the animal is merely intolerant of the mitotane (post-ACTH stimulation test cortisol is within the desired range) then simply dividing the weekly mitotane into smaller, more frequent doses may decrease the undesirable effects of this problem.
Trilostane (Vetoryl® in the UK)
General Information:
Trilostane acts as a competitive inhibitor of the 3ß-hydroxysteroid dehydrogenase enzyme system and inhibits the synthesis of several steroids, including circulating cortisol and aldosterone (see pathways, above for effects on cortisol). The effects on electrolytes (via aldosterone) is not considered clinically significant.
According to one paper (Am J Vet Res 65[9]:1245-50 2004 Sep ), "...serum aldosterone concentrations after ACTH stimulation were significantly lower than corresponding concentrations before initiation of treatment. The overall effect of trilostane on serum aldosterone concentration was less pronounced than the effect on serum cortisol concentration. Median potassium concentrations increased (only) slightly after initiation of treatment with trilostane."
Unlike mitotane, trilostane does not destroy adrenal gland tissue; its effects are reversible with discontinuation of the drug.
The drug appears to be highly efficaceous with beneficial effects seen in 82% to 97% of treated dogs.
Safety:
The drug is considered generally safe
Mild lethargy and decreased appetite are sometimes seen, usually 2-5 days after initiation of therapy but usually resolves within a week or so.
Mild elevations of serum calcium and potassium, bilirubin as well as blood urea nitrogen have been reported but have not been considered to be of clinical significance.
There is large variability in the response of individual dogs to dose and frequency of administration.
The drug has been used primarily for PDH; however one case report (Sm Anim Clin Endocrinol 14[1]:35-36 Jul'04) demonstrated efficacy in a single animal diagnosed with adrenal neoplasia (ADH) and resulting hyperadrenocorticism
The drug is not yet (as of August 2005) approved for use in the United States; however FDA approval on a case by case basis is possible, though some delay in obtaining the medication is to be expected, as the wheels of beaurocracy move slowly.
Treatment Protocol:
The initial dose and frequency is somewhat variable. Early studies suggested starting (once daily) doses, depending on the weight of the animal, as follows:
< 5 kg 30 mg/24 hr
5-20 kg dogs, 60 mg/24h
20-40 kg dogs, 120 mg/24h
>40 kg dogs, 240 mg/24h
More recently, studies suggest that the maximum effects do not last 24 hours, and that dosing should be twice daily, intially dosing at ~ 6 mg/kg twice daily (or as close to this dose as the available capsule sizes permits)
Note that the dose will probably have to be adjusted, depending on the results of ACTH stimulation tests (see below, Monitoring); doses as high as 40 -50 mg/kg have been given without significant side effects.
One paper suggestes that most animals will probably require 19 mg/kg/day (~9.5 mg/kg twice daily); another paper states that final doses ranged from 3 mg/kg twice daily to 16 mg/kg twice daily.
Monitoring the Response to Treatment:
Perform an ACTH stimulation test (and electrolyte levels) two weeks after intiating therapy, 4-6 hours after dosing.
Adjust the Trilostane dose as follows:
If the post-ACTH stimulation cortisol level is less than 1 µg/dl, stop the trilostane for 48 hours, then reintroduces at the next smaller capsule size; repeat testing in two weeks.
If the post-ACTH stimulation cortisol level is greater than 4.3 µg/dl, then increase each dose of trilostane to the next larger capsule and repeat testing in two weeks.
If the post-ACTH stimulation cortisol level is greater than 1 µg/gl but less than 4.3 µg/dl, continue with the current dose; recheck of ACTH stimulation results and electrolytes should be performed every 3-4 months
Ketoconazole
General Information:
This is used primarily for it's antifungal properties. It's use in the treatment of PDH are unrelated to it's antifungal properties
It works to inhibit the enzymatic system in the adrenal gland that produces glucocorticoid hormones.
Only about 30% to 50% of dogs with PDH respond to ketoconazole
There are side effects...especially associated with inflammation in the liver...vomiting, diarrhea, inappetance... that may require avoidance of this drug, or discontinuation of ongoing treatment.
Treatment Protocol:
Beginning dose is 10mg/kg twice daily for 14 days.
An ACTH Stimulation Test is then performed...results for pre- and post ACTH adminstration should both approximate normal basal cortisol levels, as described for Mitotane, above.
If the ACTH stimulation Test does not indicate the desired response, the dose of ketoconazole is increased to 15mg/kg twice daily, for 14 days and the ACTH Stimulation test is repeated. If the response is unsatisfactory, the dose may be increased to 20mg/kg twice daily....but a higher dose is more likely to reap the untoward side effects, including liver toxicity, vomiting, diarrhea, anorexia.
In some animals, treatment can cause acute glucocorticoid deficiency, like treatment with mitotane...and this can result in a rapid destabilization, shock and death. This can be reversed with prednisolone supplementation (as described above for mitotane) or discontinuation of the drug.
Selegiline hydrochloride:
General Information:
is also called levodeprenyl, L-deprenyl, deprenyl and (the veterinary product) Anipril.
has also been used to treat dimentia in dogs (i.e. cognitive disorder).
the rationale for using selegiline stems from information that an aberration in the neurotransmitter dopamine is involved in the development of Cushing's Disease (PDH) that results when a certain portion of the pituitary gland (the pars intermedia) is affected. It is not effective when other portions of the pituitary are responsible for PDH
selegiline is a selective monoamine oxidase type B inhibitor which helps to maintain or restore dopamine concentrations in the central nervous system, at least experimentally.
selegiline does not affect the adrenal gland and it does not inhibit adrenal gland activity, including the synthesis of corticosteroids. It is considered VERY safe (unlike mitotane and ketoconazole)
the response of PDH dogs to selegiline is controversial at best:
anywhere from 20% (one study) to 83% (another study) of treated dogs showed some response, based upon improvement in clinical signs associated with hyperadrenocorticism.
some dogs showed increased activity during treatment, but whether this was due to a decrease in pituitary pathology...or to the increase in circulating amphetamine concentration (as a result of the normal body breakdown of selegiline) is debatable.
there is some...but not much...evidence that in some dogs responding to the drug, the pituitary mass may actually shrink!
because the efficacy is low (20% seems to be the common concensus), the drug should be reserved to animals in which the disease is mild, is progressing slowly and the animal can afford the three month trial before proceding to other treatments.
Treatment Protocol:
initial dose of the drug is 1mg/kg per day in the morning.
a response to treatment is determined by improvement in the clinical signs (NOT the results of an ACTH Stimulation test...since the drug does not affect the adrenal gland!)
if there is failure to show a response in 2 months, the dose is increased to 2mg/kg per day. for additional one month
if no response at the higher dose is observed, then an alternative treatment must be considered.
if the response is considered successful, the animal takes the drug for the rest of it's life.
Adrenal-Dependent Hyperadrenocorticism (ADH)
Mitotane (Lysodren® , o,p'-DDD)
General Information
the preferred, most successful treatment of ADH is surgery (discussed elsewhere ).
for other general comments, please see the discussion of mitotane in the treatment of PDH, above)
induction and maintenance doses for successful treatment of ADH are significantly greater than for PDH.
when successful, ADH dogs treated with mitotane lived an average of 11.5 months; but only 56% of ADH dogs respond to mitotane at any dose.
generally, a loading dose of 50-75mg/kg per day is required and the ACTH Stimulation Test is done sooner (5-7 days after beginning induction phase...sooner if clinical signs of toxicity are seen (see mitotane protocol for PDH, above)
if no response, the treatment is continued another 5-7 days...if still no response, the dose of mitotane is increased by 20mg/kg per day, and the cycle described here is repeated.
maintenance, (if induction is successful) requires 50-100mg/kg per week, divided over two or three days per week.
some animals need low doses of prednisolone during the induction and/or the maintenance phases to avoid clinical signs of hypoadrenocorticism.
ACTH Stimulation Tests are repeated at one month then every three months....relapse rates are high, and repeating the induction phase is sometimes necessary.
