Tuesday, September 24, 2013

Performing an ACTH Stimulation Test in Dogs Treated with Fludrocortisone (Florinef)

Fludrocortisone acetate (Florinef), a drug used as mineralocorticoid replacement in dogs with primary hypoadrenocorticism (Addison's disease) 

Thanks for your last post on "Confirming the Diagnosis of Addison's Disease after Treatment of an Adrenal Crisis." I found it to very helpful in managing these dogs in my practice. However, after reading it, I have 2 questions:
  1. Are you at all concerned about the glucorticoid effect of fludrocortisone (Florinef) and its effect on the hypothalamic-pituitary-adrenal (HPA) axis?
  2. Will fludrocortisone cross-react in the cortisol assay to falsely elevate the measured cortisol result? I've read that the cross reaction is limited to 6% or less — is that correct?
  3. How long would I have to stop this drug before I do an ACTH stimulation test in a dog suspected of having Addison's disease?
My Response:

All of your questions are good ones. When we consider mineralocorticoid replacement for dogs with Addison's disease, we have two choices — fludrocortisone acetate (Florinef), administered orally on a daily basis, or desoxycorticosterone pivalate (Percorten-V) generally administered by injection every 3-5 weeks (1-3).

Fludrocortisone acetate is a synthetic adrenocortical steroid that has potent mineralocorticoid and glucocorticoid activities. Compared to cortisol, this drug has 125-times the mineralocorticoid activity and has 10-times the glucocorticoid activity. In this regard, fludrocortisone is very different than desoxycorticosterone pivalate, which is a pure mineralocorticoid agent and possesses no glucocorticoid activity.

The potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polyuria and other signs of iatrogenic Cushing's syndrome, especially when on high daily doses of the drug. It also is the reason why many dogs treated with fludrocortisone do not require additional daily prednisone or prednisolone supplementation.

Because of its glucocorticoid activity, fludrocortisone will indeed cross-react in the cortisol assay to a some extent, as you noted. But even more importantly, it can suppress the HPA axis, especially when given in large doses (4,5), and may lead to a lowering of the basal cortisol concentration and blunting of the cortisol response to ACTH stimulation.

Ideally, we would do the ACTH stimulation test early in the course of the disease, before the dog has been treated for more than a few days with fludrocortisone but especially before the drug dosage has been increased to high daily levels. In these dogs, I simply withhold the drug for 24 hours prior to doing the ACTH stimulation test. That time interval will allow most of the drug to be eliminated so we don't have to worry about measuring the fludrocortisone in the cortisol assay.

If a dog has been on long-term and high-dose fludrocortisone therapy, it is always a good idea to switch to Percorten-V therapy for their mineralocorticoid supplementation for a month or two prior to ACTH stimulation testing. Because Percorten doesn't have any glucocorticoid activity, this might allow the HPA to recover if it has been chronically suppressed by the high-dose fludrocortisone therapy.

References:
  1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
  2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
  3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;in press.
  4. Otte C, Jahn H, Yassouridis A, et al. The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone. Life sciences 2003;73:1835-1845. 
  5. Karamouzis I, Berardelli R, Marinazzo E, et al. The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic-pituitary-adrenal (HPA) axis in humans. Pituitary 2013;16:378-385. 

6 comments:

Lori B said...

Hello Dr. Peterson,

You mention the comparison between Florinef & cortisol. Would you be able to state what the glucocorticoid equivalent would be to Prednisone. For example, would you say that the glucocorticoid amount in each 0.1mg tablet is equivalent to roughly 0.25mg of Pred, or would it be some other value?

Also, on a slightly different topic, since Prednisone has relatively little mineralcorticoid effect, how much Prednisone would need to be given before it has any effect on the electrolytes. I understand that Prednisone should not be used to control the electrolytes. I'm just interested, theoretically, in how much would have to be given to have any effect. So, for example, would 5mg of daily Prednisone have any effect on the electrolytes of a 65 pound dog - or would the amount need to be significantly higher?

Thank you,
Lori

Dr. Mark E. Peterson said...

Florinef seems to have an individualized effect in dogs, so we can't predict how much glucocorticoid effect we will see. However, most dogs that are getting more that 0.1 mg per 10 pounds of body weight will likely need to have the prednisone dosage decreased slightly.

Prednisone has absolutely no mineralocorticoid activity and has no effect on serum electrolytes.

craig sharpe said...

Hi Dr Petterson, I have a 9 year old black lab that was diagnosed with addisons last November. Her na k ratio was 24 and was given a 2 ml shot of percorten. 8 days later I has acth stim test done and addison's was confirmed. I changed vets 4 months ago because I couldn't convince vet that prednisone was necessary for positive result. I had lytes checked with new vet 1st visit and he told me she had normal lytes at 30 days and she was getting 1.8 ml. He raised her dosage to 2.5 ml every 28 days. After 4 month I finally got him to reduce dose to 2 ml after a 12 day lyte test come back 39 ratio and 29 day at 37. I am thinking she has secondary or atypical addisons and doesn't need much percorten. What are your thoughts on amount and weather or not she even should have gotten a shot on day 29 with that ratio?

Dr. Mark E. Peterson said...

what were the actual potassium and sodium concentrations?

craig sharpe said...

Thanks for getting back to me. Na 155 k 4.2.

Dr. Mark E. Peterson said...

Well, we normal serum electrolytes, you could make a diagnosis of primary hypoadrenocorticism without measuring either plasma ACTH levels or serum aldosterone concentrations. If that was not done, then you really can't make a diagnosis of classic Addison's disease.

Based on what you have given me, I'm not even sure if you dog has an adrenal problem at all and I would not be able to determine that without a complete history, doing more lab work and seeing your dog, etc. I'd recommend you talk to your vet but you might need a second opinion with a specialty to work out exactly what's going on and what medication is needed (if any).