An 11-year-old neutered male Pomeranian with diabetes mellitus (well controlled for 2 years with q12h NPH insulin and a high-fiber diet) is presented with intermittent inappetence, small-bowel diarrhea, and weight loss of 2 months’ duration. There is no history of diet change/indiscretion or known infectious disease exposure. Physical examination, CBC, serum chemistry profile, serum fructosamine, urinalysis, baseline cortisol, cPLI test, and abdominal imaging (radiography and ultrasonography) rule out diabetic dysregulation, pancreatitis, GI obstruction, and hypoadrenocorticism. Fecal analysis findings are unremarkable. Signs do not resolve with empiric anthelmintic (ie, fenbendazole) administration, additional dietary fiber, antibiotic administration, and an 8-week limited-antigen diet trial. Endoscopy is performed; endoscopic intestinal biopsies show lymphoplasmacytic enteritis, and inflammatory bowel disease (IBD) is diagnosed.
Which of the following drugs would be appropriate in the management of this patient?
Based on the information provided, how would you grade the following drugs and why?
Correct ResponseSafeMetronidazole is not an antidiarrheal agent, although it is sometimes misused as such. Metronidazole does, however, have antimicrobial activity against many potential GI pathogens (eg, Clostridium spp, Helicobacter spp, Entamoeba spp, Balantidium spp, Giardia spp). It is also used as adjunctive treatment for hepatic encephalopathy to reduce populations of gut bacteria (particularly proteolytic anaerobes) that generate ammonia and to treat GI dysbiosis, which may arise secondary to many intestinal or extraintestinal diseases. Empiric administration of metronidazole, tylosin, or tetracycline is used in patients with chronic diarrhea to assess for antibiotic-responsive diarrhea.
Metronidazole demonstrates an immunomodulating effect by suppressing cell-mediated immunity, an effect that is exploited by its use in suppressing inflammation and in treating IBD, potentially reducing the need for corticosteroids or other potent immunosuppressive agents. Metronidazole has a bitter taste to which patients may vehemently object, so administration in pill pockets or in flavored compounded suspensions may be necessary; however, flavorings and other food antigens can interfere with dietary control measures in patients being fed hypoallergenic diets and those participating in diet trials. Adverse effects include anorexia (particularly problematic in a diabetic animal), vomiting, diarrhea, and, of importance, a wide variety of neurologic abnormalities (eg, ataxia, nystagmus, head tilt, tremors, disorientation, seizures) that may be seen acutely or with chronic administration. Incidence of adverse effects may be reduced by avoiding use of higher doses or prolonged administration, but adverse neurologic effects may be seen in some patients after short-term administration of lower doses. Mutagenic effects of metronidazole administration have been demonstrated in multiple species, including humans and cats,1 and should be considered when using the medication.
Concurrent administration of metronidazole and cyclosporine may result in increased cyclosporine levels. Metronidazole has been implicated in 2 human case reports as a cause of significant increases in plasma cyclosporine levels when administered with cyclosporine.2,3 Mild inconsequential (6%) reduction of cyclosporine metabolism by metronidazole was identified in a study of cytochrome enzyme CYP3A activity in human liver microsomes,4 but there is little evidence further documenting this interaction. There are no reports of a metronidazole–cyclosporine interaction in other species; however, based on the reports in the human literature, clinicians should be aware of the potential for this interaction when considering concurrent use of these drugs in veterinary patients.
Correct ResponseSafeProbiotics are live micro-organisms that are administered orally to beneficially alter intestinal flora, improve intestinal mucosal function, and moderate intestinal immune responses. Probiotics have been beneficial in treating dogs with acute and chronic diarrheal diseases and are generally considered safe.5-8 Manipulation of the gut microbiome using prebiotics (ie, dietary agents that are substrates for beneficial bacteria and promote their growth) in diabetic humans has resulted in improved glucose tolerance and reduced markers of inflammation.9-11 Potential benefits of manipulating gut bacterial populations in diabetic dogs have not been studied.
Correct ResponseSafeHypocobalaminemia may develop in patients with intestinal disease either resulting from reduced absorption of dietary cobalamin by the impaired intestine or because of increased numbers of intestinal bacteria that bind luminal cobalamin and prevent its absorption. Cobalamin deficiency may manifest clinically as a suboptimal response to treatment for intestinal disease or, less commonly, with systemic manifestations of anemia, neutropenia, or neurologic abnormalities. Commercial testing for evaluation of serum cobalamin levels is available to identify patients with hypocobalaminemia requiring supplementation. Cobalamin is most commonly administered parenterally to circumvent problems with intestinal absorption, but recent work demonstrates that oral administration may adequately correct cobalamin deficiencies in dogs.12
Correct ResponseSafeContinued use of an insulin that has been effective in treating this dog’s diabetes is recommended. However, if treatment with prednisone, prednisolone, or cyclosporine is initiated to manage IBD, the dose may need to be increased to overcome insulin antagonism by these drugs, and more frequent monitoring of weight, clinical signs, and parameters of glycemic control is warranted to identify changes in insulin dose requirements. The insulin dose should not be changed unless glycemic control is lost; the effect of insulin antagonist drugs may not be manifested immediately and may take weeks to months to become apparent.
Treatment for IBD may result in improved appetite, nutrient absorption, and gut motility, all of which may impact the insulin dose required to maintain control of diabetes mellitus. Diet change is key in diagnostic assessment and long-term management of chronic diarrheal diseases; any diet change will impact insulin requirements of the diabetic animal, so disruption of current glycemic control is likely in the course of evaluating and treating this patient.
Correct ResponseCautionNo evidence exists that any particular type of insulin is less affected by the insulin antagonism of corticosteroids or cyclosporine; therefore, continued use of the current NPH insulin is recommended. Changing to another insulin type should be avoided unless diabetes mellitus becomes persistently unregulated on the current insulin despite appropriate dose adjustments and control of concurrent IBD. As compared with NPH insulin, glargine is a longer-acting insulin and may be considered if NPH’s duration of action is inadequate for q12h administration or if the condition becomes refractory to NPH.13
Correct ResponseDo Not UseGlipizide is an oral hypoglycemic agent believed to trigger increased release of exogenous insulin from functioning pancreatic β cells. It is sometimes used to treat diabetic cats,14 in which diabetes typically parallels type 2 diabetes in humans, with a significant remaining functional β cell mass. However, it is not indicated for treating diabetic dogs.
Prednisone or prednisolone
Correct ResponseCautionOral corticosteroids are widely used to control intestinal inflammation in the initial stages of IBD treatment and to treat flares. In patients with severe disease, treatment may be initiated with injectable corticosteroids to circumvent problems with absorption secondary to significantly disrupted gut function. Corticosteroids are initiated at immunosuppressive doses, followed by tapering doses over several months. Because of the high doses and extended period of administration generally followed, corticosteroid administration is expected to result in insulin antagonism and disruption of this dog’s diabetic control, and adjustments in insulin doses will likely be needed. Ongoing adjustments as corticosteroid doses are sequentially reduced should also be anticipated; as a result, more intensive monitoring of this dog’s diabetes will be required until IBD is controlled and corticosteroid administration is discontinued or reduced to a stable maintenance level. Although corticosteroids can complicate diabetic management, they offer an advantage in their primary appetite-stimulant effect, in addition to improvements in appetite resulting from control of intestinal inflammation from IBD; both help diabetic patients maintain an appetite, which is critical in stabilizing glycemic control.
Correct ResponseSafeBudesonide is a potent glucocorticoid that, when administered orally, is well absorbed in dogs with IBD.15
It undergoes high first-pass hepatic metabolism, which reduces systemic drug levels and therefore systemic adverse effects such as insulin antagonism. Still, budesonide has systemic effects—which are reduced but not eliminated—and, like prednisone or prednisolone, there remains the potential for withdrawal effects if it is discontinued suddenly. This drug has a topical anti-inflammatory effect at the intestinal mucosa that does not require absorption and recirculation to the gut. Budesonide is more expensive than prednisone or prednisolone and is available in formulations for humans; compounding the medication for appropriate dosing in small animals can add cost and make it more difficult to taper the dose. When compounding, it is important to preserve the integrity of the enteric-coated spheres inside the capsules. Budesonide is an excellent alternative to corticosteroids for treatment of IBD in a diabetic dog.16
Correct ResponseCautionCyclosporine may be used as a primary or adjunctive immunosuppressive agent in patients with IBD and has been used successfully to treat some dogs with steroid-refractory IBD.17
Cyclosporine has been shown to have toxic effects on the pancreas in several species, including dogs,18 that can cause β cell destruction, reduced insulin secretion, and insulin resistance resulting from dyslipidemia and reduced activity of genes involved in insulin action and glucose uptake. Therefore, cyclosporine likely offers no advantage over glucocorticoids for use as an immunosuppressive agent in diabetic patients. Also, addition of cyclosporine to the treatment regimen for patients already receiving glucocorticoids introduces additional insulin antagonism, with the potential to precipitate diabetes mellitus in a patient not previously diabetic as well as to further disrupt diabetic regulation in an existing diabetic patient. Concurrent use of corticosteroids, calcium-channel blockers, omeprazole, or metronidazole may increase cyclosporine levels and risk for cyclosporine toxicity. Interaction with antihypertensive drugs, including amlodipine, can result in significantly increased plasma cyclosporine levels in humans and rats and may therefore increase the risk for adverse effects of cyclosporine, such as nephrotoxicity.19-22 Neither of these drug–drug interactions nor cyclosporine-induced nephrotoxicity has been documented in dogs. Signs of cyclosporine toxicity in dogs (ie, inappetence, vomiting, diarrhea) may overlap with signs of poorly controlled IBD or diabetic ketoacidosis, for which this dog must be monitored. Cyclosporine is a poor choice for initial or adjunctive treatment for IBD in a diabetic dog.
Correct ResponseCautionSystemic hypertension is a relatively common comorbidity in patients with diabetes mellitus.23 Blood pressure should be assessed initially and monitored regularly. Hypertension may also manifest in animals with corticosteroid excess, as seen with endogenous hypercortisolism (ie, Cushing’s disease) or administration of moderate-to-high doses of exogenous corticosteroids, and is associated with cyclosporine administration in humans.20 In this patient, hypertension may be present as a diabetic comorbidity or may arise or worsen secondary to administration of corticosteroids or, potentially, cyclosporine. Systolic pressure should be maintained <180 mm Hg, and antihypertensive agents may be needed.
Amlodipine is a calcium-channel blocker used to treat hypertension in dogs. It is typically used as adjunctive therapy and added after use of an ACE inhibitor (eg, benazepril, enalapril) has failed to fully control blood pressure. Amlodipine may increase cyclosporine levels if cyclosporine is used to treat this patient’s IBD; this effect has been well documented in humans but not reported in dogs.19,20 Adverse effects of amlodipine include GI signs (eg, inappetence, vomiting), which may overlap with signs of uncontrolled diabetes mellitus (eg, diabetic ketoacidosis) or IBD.
Correct ResponseDo Not UseAminopentamide is an anticholinergic agent that blocks activation of smooth muscle contraction, thereby reducing GI motility. In most patients with diarrhea, GI motility is already reduced, and further suppression of motility with an anticholinergic agent is contraindicated. GI motility is also reduced in diabetic patients; further reduction caused by an anticholinergic agent is contraindicated and may complicate glycemic control by altering the rate of delivery and absorption of nutrients.
- Sekis I, Ramstead K, Rinshiw M, et al. Single-dose pharmacokinetics and genotoxicity of metronidazole in cats. J Feline Med Surg. 2009;11(2):60-68.
- Herzig K, Johnson DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant. 1999;14(2):521-523.
- Zylber-Katz E, Rubinger D, Berlatzky Y. Cyclosporine interactions with metronidazole and cimetidine. Drug Intell Clin Pharm. 1988;22(6):504-505.
- Maurice M, Pichard L, Daujat M, et al. Effects of imidazole derivatives on cytochrome P450 from human hepatocytes in primary culture. FASEB J. 1992:6(2):752-758.
- Bybee SN, Scorza AV, Lappin MR. Effect of the probiotic Enterococcus faecium SF68 on presence of diarrhea in cats and dogs housed in an animal shelter. J Vet Intern Med. 2011;25(4):856-860.
- Herstad HK, Nesheim BB, L’Abée-Lund T, Larsen S, Skancke E. Effects of a probiotic intervention in acute canine gastroenteritis—a controlled clinical trial. J Small Anim Pract. 2010;51(1):34-38.
- Sauter SN, Benyacoub J, Allenspach K, et al. Effects of probiotic bacteria in dogs with food responsive diarrhea treated with an elimination diet. J Anim Physiol Anim Nutr (Berl). 2006;90(7):269-277.
- Rossi G, Pengo G, Caldin M, et al. Comparison of microbiological, histological, and immunomodulatory parameters in response to treatment with either combination therapy with prednisone and metronidazole or probiotic VSL#3 strains in dogs with idiopathic inflammatory bowel disease. PLoS One. 2014;9(4):e94699.
- He C, Shan Y, Song W. Targeting gut microbiota as a possible therapy for diabetes. Nutr Res. 2015;35(5):361-367.
- Firouzi S, Majid HA, Ismail A, Kamaruddin NA, Barakatun-Nisak MY. Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial. Eur J Nutr. 2016;[Epub ahead of print].
- Zhang Q, Wu Y, Fei X. Effects of probiotics on glucose metabolism in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Medicina (Kaunas, Lithuania). 2016;52(1):28-34.
- Toresson L, Steiner JM, Suchodolski JS, Spillmann T. Oral cobalamin supplementation in dogs with chronic enteropathies and hypocobalaminemia. J Vet Intern Med. 2016;30(1):101-107.
- Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc. 2013;243(8):1154-1161.
- Feldman EC, Nelson RW, Feldman MS. Intensive 50-week evaluation of glipizide administration in 50 cats with previously untreated diabetes mellitus. J Am Vet Med Assoc. 1997;210(6):772-777.
- Pietra M, Fracassi F, Diana A, et al. Plasma concentrations and therapeutic effects of budesonide in dogs with inflammatory bowel disease. Am J Vet Res. 2013;74(1):78-83.
- Dye TL, Diehl KJ, Wheeler SL, Westfall DS. Randomized, controlled trial of budesonide and prednisone for the treatment of idiopathic inflammatory bowel disease in dogs. J Vet Intern Med. 2013;27(6):1385-1391.
- Allenspach K, Rüfenacht S, Sauter S, et al. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. J Vet Intern Med. 2006;20(2):239-244.
- Ishizuka J, Gugliuzza KK, Wassmuth Z, et al. Effects of FK506 and cyclosporine on dynamic insulin secretion from isolated dog pancreatic islets. Transplantation. 1993;56(6):1486-1490.
- Bernard E, Goutelle S, Bertrand Y, Bleyzac N. Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children. Ann Pharmacother. 2014;48(12):1580-1584.
- Cai J, Huang Z, Yang G, et al. Comparing antihypertensive effect and plasma ciclosporin concentration between amlodipine and valsartan regimens in hypertensive renal transplant patients receiving ciclosporin therapy. Am J Cardiovasc Drugs. 2011;11(6):401-409.
- Kumar NP, Inamdar MN, Venkataraman BV. Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats. Indian J Exp Biol. 2007;45(7):638-641.
- Cavarape A, Endlich K, Feletto F, Parekh N, Bartoli E, Steinhausen M. Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats. Kidney Int. 1998;53(4)53:963-969.
- Herring IP, Panciera DL, Were SR. Longitudinal prevalence of hypertension, proteinuria, and retinopathy in dogs with spontaneous diabetes mellitus. J Vet Intern Med. 2014;28(2):488-495.
- Plumb DC. Plumb’s Veterinary Drug Handbook. 8th ed. Stockholm, WI: PharmaVet; 2015.
- Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: a meta-analysis of randomised placebo-controlled trials. Br J Nutr. 2016;115(7):1167-1177.
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