Ketoconazole-induced transient hypoadrenocorticism in a dog

Abstract

A 6-year-old, spayed female, mixed breed boxer dog was presented for decreased appetite, polyuria and polydipsia, and lethargy 9 days after treatment with ketoconazole for Malassezia pododermatitis. Ketoconazoleinduced hypoadrenocorticism was confirmed with an adrenocorticotropic hormone (ACTH) stimulation test, and ketoconazole was discontinued. Clinical signs resolved 48 hours after initiation of prednisone, and resolution of glucocorticoid insufficiency was confirmed with a repeat ACTH stimulation test 48 hours after a 10-day course of prednisone. Glucocorticoid insufficiency after administration of a commonly used dermatological dose of ketoconazole has not been previously reported in veterinary medicine but should be considered in patients with adverse effects while receiving ketoconazole.

Key clinical message:

Iatrogenic hypoadrenocorticism may occur in dogs treated with commonly used dermatological doses of ketoconazole. The disease is likely transient, but steroid supplementation may be required in some patients to resolve clinical signs, especially in the presence of concurrent illness or stress.

Ketoconazole is an imidazole antifungal drug that prevents synthesis of the essential cell wall component ergosterol by inhibition of the cytochrome P450 enzyme lanosterol 14α-demethylase (1). Historically, ketoconazole was used for systemic fungal infections, but newer triazoles such as itraconazole and fluconazole are now preferred due to superior efficacy (1). Ketoconazole remains an effective treatment for canine Malassezia dermatitis and dermatophytosis at a dosage of 5 to 10 mg/kg body weight (BW), q24h for 21 d (1). Adverse effects of ketoconazole occur in 10% to 15% of dogs, and although more common at higher dosages, adverse effects may also be independent of dosage (2). Common side effects include gastrointestinal upset, cutaneous drug reactions, and liver enzyme elevation (2). Hepatotoxicity has been reported and is typically reversible after discontinuing ketoconazole (1). However, at a daily dose of 80 mg/kg BW, icterus and death have occurred (2). Ketoconazole potently inhibits the P450 enzyme CYP3A and p-glycoprotein and therefore may cause significant drug interactions (1).

Although not a preferred treatment due to poorer efficacy, ketoconazole may be used to treat hyperadrenocorticism, as it inhibits cortisol synthesis via inhibition of cytochrome P450 enzymes in the adrenal cortex (3). Adequate control of clinical signs of canine hyperadrenocorticism usually requires dosages significantly higher (10 to 30 mg/kg BW, q12h) than standard anti-fungal doses (5 to 10 mg/kg BW, q24h) (3–6). Signs of cortisol insufficiency in dogs treated with ketoconazole are, therefore, not expected with commonly used dermatological doses (3–5). However, ketoconazole-induced adrenal insufficiency has been described in humans (7,8). To the authors’ knowledge, this is the first report of hypoadrenocorticism in a dog due to ketoconazole administration to treat a fungal infection.

Case description

A 6-year-old, spayed female, 20 kg mixed breed boxer dog was presented to the internal medicine service at Mississippi State University Animal Health Center with a 1-week history of profound polyuria and polydipsia (PU/PD), decreased appetite, and lethargy. The dog had a history of atopic dermatitis and had received oral hydroxyzine (Vistaril; Harris Pharmaceutical, Fort Myers, Florida, USA), 2.3 mg/kg BW, q8h, for pruritus. She also had a history of separation anxiety and was treated with fluoxetine (Prozac; Morris and Dickson, Shreveport, Louisiana, USA), 1 mg/kg BW, q24h. Except for monthly ivermectin/ pyrantel (Heartgard; Boehringer Ingelheim, Duluth, Georgia, USA), the patient had not received any other medications, including glucocorticoids, or undergone any anesthetic procedures for at least 2 mo before presentation. At the time of presentation, she had been receiving ketoconazole (Nizoral; Mylan Pharmaceuticals, Canonsburg, Pennsylvania, USA), 4.5 mg/kg BW, q12h for 9 d for Malassezia pododermatitis. The owner noted an increase in the dog’s water consumption 2 d after starting the ketoconazole (Figure 1), and the dog also had urinated 3 times in the house over the last week. The urine appeared clear, and the amount was normal to increased, according to the owner. No dysuria was noted. Four days prior to presentation to the internal medicine service, the dog was evaluated for the suspected polyuria and polydipsia (PU/PD) by the community veterinary service at Mississippi State University Animal Health Center. At that time, the dog had received ketoconazole for 5 d. A urinalysis revealed a urine specific gravity of 1.008 and an inactive sediment. A urine culture yielded no bacterial growth after 48 h. The dog was then referred to the internal medicine service at Mississippi State University Animal Health Center.

Figure 1.

Timeline of clinical signs and administration of medication. D — day of therapy; KTZ — ketoconazole; rDVM — referring veterinarian; UA — urinalysis; C/S — urine culture and sensitivity; Chem — serum chemistry; ACTH stim — adrenocortcotropic hormone (ACTH) stimulation test.

On presentation to the internal medicine service, the dog was bright and alert with normal vital parameters. She postured normally and urinated a large amount of clear urine on the clinic floor during the examination. A weight loss of 1 kg over the previous 9 d was noted. A serum chemistry profile revealed moderately increased creatinine [194.5 μmol/L; reference interval (RI): 44.2 to 123.8 μmol/L]. The blood urea nitrogen, alkaline phosphatase, alanine aminotransferase, bilirubin, albumin, and electrolytes were within normal reference ranges. A repeat urinalysis was not performed, as the dog had completely voided her bladder upon presentation. No significant abnormalities were found on abdominal ultrasound. A baseline cortisol measured with a chemiluminescent immunoassay (Immulite; Siemens Healthineers, Germany) was 27.6 nmol/L. One hour following intravenous administration of cosyntropin, (Cortrosyn; Amphastar Pharmaceuticals, Rancho Cucamonga, California, USA), 5 μg/kg BW, the serum cortisol concentration was 27.6 nmol/L, confirming hypoadrenocorticism. Results of the baseline cortisol were available at the end of the day on a Friday, so results of the ACTH stimulation test were not available until the following Monday (12 d after ketoconazole was started; Figure 1). The patient had not received any glucocorticoids that might interfere with ACTH simulation results for at least 2 mo prior to presentation.

Glucocorticoid insufficiency secondary to ketoconazole was suspected, but not confirmed; therefore, oral prednisone (PredniSONE; Boehringer Ingelheim; Koln, Germany), 0.38 mg/kg BW, q24h, was started on day 12. Ketoconazole was continued to complete the 2-week course to treat pododermatitis and the last dose was given the morning of day 14, 2 d after prednisone treatment had been initiated. The dog’s appetite and PU/PD improved the morning after prednisone was started (day 13), and these signs were completely resolved within 48 h (the morning of day 14), prior to her final dose of ketoconazole. Prednisone was tapered to 0.25 mg/kg BW, q24h after 3 d. Repeat ACTH stimulation test with the same immunoassay 48 h after completing a 10-day course of oral prednisone confirmed resolution of hypoadrenocorticism (pre-ACTH cortisol < 27.6 nmol/L; post-ACTH cortisol 157.3 nmol/L) (Table 1). The dog’s body weight had increased to 21 kg and she continued to do well without glucocorticoids; the clinical signs of hypoadrenocorticism did not return. Six months after initial presentation, electrolytes and ACTH stimulation results were within the reference ranges (pre-ACTH 69.0 nmol/L; post- ACTH 350.4 nmol/L) (Table 1). The dog’s CBC and serum chemistry values, including BUN and creatinine, were within the reference ranges, and her urine specific gravity was 1.029. At the time of this report, approximately 3 y after initial diagnosis of hypoadrenocorticism, the dog remains clinically normal.

Table 1.

Results of ACTH stimulation tests.

Days since KTZ treatment initiated	Pre-ACTH cortisol (nmol/L)	Post-ACTH stimulation cortisol (nmol/L)
9	< 27.6	< 27.6
24	< 27.6	157.3
180	69.0	350.4

KTZ — ketoconazole; ACTH — adrenocorticotropic hormone.

Discussion

This is the first documented report of ketoconazole-induced transient hypoadrenocorticism in the dog. Of interest is the relatively low dosage (4.5 mg/kg BW, PO, q12h) at which clinical signs of adrenal insufficiency occurred. In a study by Feldman et al (3), little or no reduction in cortisol levels occurred at 5 mg/kg BW, q12h (3). At higher dosages, ketoconazole inhibits cortisol synthesis in the adrenal cortex primarily via blockade of 11-hydroxylase and is consequently a commonly used medical treatment for pituitary-dependent hyperadrenocorticism (HAC) in humans (4,9). Ketoconazole is also used by some veterinarians to treat canine HAC, but dosages up to 20 to 30 mg/kg BW, q12h may be required to control clinical signs (4–6).

In contrast to veterinary medicine, ketoconazole-induced adrenal insufficiency has been reported in humans (7,8). Clinical symptoms of transient adrenal insufficiency in humans have been documented (7). In a study of 10 children receiving a long-term (3 to 52 mo), single morning dose of 10 to 23 mg/kg BW for coccidioidomycosis, ACTH-stimulated cortisol levels 4 h after ketoconazole administration were variably suppressed compared to normal values (8). The mean cortisol response to ACTH had increased significantly 24 h after ketoconazole administration (8). In contrast, irreversible hypoadrenocorticism occurred in a 61-year-old female treated for blastomycosis with 200 mg of ketoconazole twice daily (7). Clinical signs developed 2 d after starting ketoconazole and resolved within 24 h after initiating glucocorticoid therapy (7). Treatment for hypoadrenocorticism remained necessary for the entire 2-year follow-up period after discontinuation of ketoconazole (7).

Unfortunately, aldosterone concentrations were not measured in our patient. Although ketoconazole inhibits several other enzymes involved in cortisol synthesis, it does not typically inhibit aldosterone synthase (CYP11B2), even at dosages of 30 to 40 mg/kg BW per day (7,9–11). Studies have shown that administration of 10 mg/kg BW per day does not affect basal and post-ACTH aldosterone levels in dogs (10,11). However, rare cases of hypoaldosteronism due to ketoconazole have been reported in both dogs and humans (7,9–11). All electrolyte concentrations were normal in our patient, but baseline and ACTH-stimulated aldosterone concentrations may be low or undetectable in dogs with hypoadrenocorticism, but without hyponatremia or hyperkalemia (12). Thus, ketoconazole-induced mineralocorticoid deficiency cannot be ruled out. Another limitation is the lack of a complete blood cell count, which was not performed due to financial constraints. Expected findings with glucocorticoid insufficiency would include lack of a stress leukogram, which is characterized by lymphopenia, neutrophilia, and/or eosinopenia, in an unwell patient (13).

Water consumption was not quantified in our patient, but the owner noticed a significant increase in water consumption and urination beginning 2 d after ketoconazole was started. The patient’s urine specific gravity was also isosthenuric. Polyuria and polydipsia (PU/PD) in canine hypoadrenocorticism are suspected to be due to hyponatremia and subsequent decreased renal medullary hypertonicity, and are therefore not easily explained in dogs with Addison’s disease without electrolyte abnormalities. However, PU/PD has been reported in many dogs with normal electrolytes and glucocorticoid-deficient hypoadrenocorticism (13,14). The mechanism for PU/PD in dogs with Addison’s disease with normal electrolytes is unknown.

Although the timing of the onset and resolution of the clinical signs in relation to the initiation of ketoconazole and prednisone, respectively, support our clinical suspicion of ketoconazole-induced hypoadrenocorticism, the authors acknowledge that other causes of lethargy, decreased appetite, and PU/PD are possible in this dog. Gastrointestinal upset and/or inappetence are common side effects of ketoconazole. Since the PU/PD resolved after ketoconazole was discontinued and prednisone therapy was initiated, it is possible that a previously unreported side effect of ketoconazole is polyuria/polydipsia. However, the PU/PD resolved on the second day of steroid supplementation, which was 1 d before discontinuation of the ketoconazole. Renal insufficiency or acute kidney injury was also considered, due to the presence of mild azotemia (elevated creatinine) and isosthenuria. However, all clinical signs and PU/PD resolved after treatment with prednisone, the patient’s creatinine was normal, and urine specific gravity was 1.029, 6 mo after presentation. To the authors’ knowledge, ketoconazole has not been reported to cause renal damage. It also seems unlikely that acute kidney injury would resolve so quickly without therapy, but this should be considered as a cause for this patient’s clinical signs and azotemia. Although a possible adverse effect of ketoconazole, hepatotoxicity was considered less likely in our patient due to absence of elevation of liver enzyme activity and/or bilirubin concentration, and cholesterol, BUN, glucose, and albumin concentrations being within the reference ranges. However, a direct test of liver function, such as an ammonia tolerance test or bile acid determination, was not performed.

At the time of diagnosis, the dog was also receiving hydroxyzine for pruritus and fluoxetine for separation anxiety. Hydroxyzine is a H1-receptor antihistamine that antagonizes histamine effect, and its most common side effect is sedation (15). Fluoxetine is a selective serotonin reuptake inhibitor antidepressant used to treat some behavioral disorders in dogs and cats. Because of changes these drugs might cause with CYP enzyme activities, their concurrent use with ketoconazole could have potentially increased ketoconazole levels, predisposing the dog to ketoconazole-related adverse effects, such as hypocortisolism. However, it is more likely that as a potent inhibitor of CYP450 enzymes, ketoconazole would have increased hydroxyzine and/or fluoxetine levels. Regardless, it is important for clinicians to consider the metabolism and clearance of medications that are used concurrently, as each medication may increase drug concentrations of another medication, predisposing the patient to adverse effects.

Rapid clinical recovery occurred with oral prednisone at approximately twice the physiological dose. The dog’s anorexia may have resolved with discontinuation of the ketoconazole alone. However, due to the confirmation of hypoadrenocorticism, we elected to treat with a short course of glucocorticoids while the patient completed the previously prescribed ketoconazole and then treat for an additional 7 d. Although the dog’s ACTH stimulation test results were low enough to cause clinical signs from hypoadrenocorticism, it is impossible to know whether the decreased appetite and lethargy were due to hypoadrenocorticism, ketoconazole, or a combination. Failure to determine aldosterone concentrations is also a limitation of this report, as these may have provided further support of a definitive diagnosis.

Ketoconazole is a commonly used imidazole drug, often prescribed for canine fungal infections, particularly Malassezia dermatitis and dermatophytosis (1). Gastrointestinal upset and decreased appetite are the most common side effects, but these adverse effects typically improve or resolve with temporary drug discontinuation, dose reduction, or administration with food (1,2). Permanent discontinuation of ketoconazole and alternative antifungal therapy may be necessary in some cases, especially if hepatotoxicity is suspected (2). Ketoconazole may be used to suppress cortisol production in hyperadrenocorticism, and the doses required to do so are variable, although typically higher than commonly used dermatological doses. The dog in this report was receiving a relatively low dose of ketoconazole for Malassezia dermatitis; however, the pharmacokinetics of ketoconazole may vary from dog to dog, similar to what is reported in humans (8). Due to the potential consequences of ketoconazole on adrenal function, even at low doses, veterinarians should also consider cortisol insufficiency as the cause of adverse effects in dogs receiving ketoconazole, particularly in a stressed patient or in patients with anxiety disorders or those receiving concurrent medications, such as the dog herein. An ACTH stimulation test is recommended if gastrointestinal signs do not resolve with drug discontinuation or if other signs of hypoadrenocorticism such as lethargy or polyuria and polydipsia occur. The incidence of ketoconazole-induced hypoadrenocorticism in dogs is unknown, but the present case increases awareness of its possibility. Based on the current human literature, ketoconazole-induced hypoadrenocorticism is likely transient in most cases, but steroid supplementation may be required in some patients to resolve clinical signs, especially in the presence of concurrent illness or stress (7,8).