Drugs Affecting Appetite (Monogastric)
Disorders of appetite are very common in veterinary patients. Obesity from overfeeding is common in companion animals and is best managed by educating the owner and regulating the animal’s diet. Anorexia is a common clinical problem seen with many systemic diseases, which exacerbates disease-induced catabolism. In the anorexic animal that does not respond to coaxing with small quantities of highly palatable foods, drug therapy may be used to stimulate appetite. The effect of specific drugs on food intake can involve hunger, satiety, or enhancement of the positive evaluation of taste.
Dirlotapide is a microsomal triglyceride transfer protein (MTP) inhibitor developed specifically for weight loss in dogs. MTP catalyzes the assembly of triglyceride-rich apolipoprotein B–containing lipoproteins to form chylomicrons in the intestinal mucosa and very low-density lipoproteins in the liver. After oral administration, dirlotapide has in vivo selectivity for intestinal MTP. The mechanism of weight loss action is not completely understood, but dirlotapide appears to reduce fat absorption and send a satiety signal from lipid-filled enterocytes. Dirlotapide also decreases appetite in a dose-dependent manner, probably via increased release of peptide YY into the circulation. The decrease in food intake is responsible for most of the weight reduction effect.
Dirlotapide is available systemically, but absorption in dogs is highly variable. Absorbed dirlotapide is metabolized in the liver; parent drug and metabolites are secreted in the bile, with potential for enterohepatic circulation. Although blood concentrations do not directly correlate with effectiveness (effectiveness has been linked to drug concentrations in the gut), they seem to correlate with systemic toxicity.
Dirlotapide is available as a 5 mg/mL solution for oral administration. The dosage is adjusted according to the weight loss of each individual dog. The initial dosage of 0.5 mg/kg is doubled after 14 days and then adjusted monthly; the maximum permitted daily dosage is 1 mg/kg, although dosages as high as 10 mg/kg have been administered to dogs without severe adverse effects in safety studies. Dirlotapide can be used without changing the dog’s current feeding or exercise regimens, but food intake should be monitored during weight stabilization to establish feeding and exercise routines that will minimize weight gain after treatment. Anorexia, emesis, and loose feces occur in some dogs. The incidence of emesis generally increases with dose and decreases with treatment time. Increases in hepatic transaminase activity were seen in dogs treated with >1.5 mg/kg/day but were not associated with clinical signs or histopathologic evidence of hepatic degeneration or necrosis.
Dirlotapide should not be used in cats. It increases the risk of hepatic lipidosis during weight loss in obese cats. Dirlotapide is not recommended for use in dogs currently receiving longterm glucocorticoid therapy or in dogs with liver disease. In people, adverse reactions associated with ingesting dirlotapide include abdominal distention, abdominal pain, diarrhea, flatulence, headache, increased serum transaminases, nausea, and vomiting.
Drugs Used to Stimulate Appetite
Anabolic steroids are synthetic derivatives of testosterone that have enhanced anabolic effects with reduced androgenic effects. Anabolic steroids do not directly affect hunger, satiety, or sensory perception of food. Instead, they antagonize the catabolic effect of glucocorticoids and the negative nitrogen balance associated with surgery, illness, trauma, and aging. In all cases, improved nitrogen balance depends on adequate protein/calorie intake and treatment of the underlying disease. Anabolic steroids stimulate hematopoiesis, appetite, and weight gain. Adverse effects of anabolic steroid therapy include hepatotoxicity, masculinization, and early closure of bony epiphyses in young animals. Anabolic steroids are contraindicated in animals with congestive heart failure because of sodium and water retention. Because of human abuse potential, anabolic steroids are controlled substances. Although once (in)famous for abuse in people and horses, stanozolol and boldenone undecylenate are no longer marketed by veterinary pharmaceutical companies in North America. Currently, any anabolic product for veterinary use can only be obtained from a compounding pharmacy. Use of anabolic steroids in performance horses is prohibited by most equine sport organizations, and detection times can be >2 mo.
Glucocorticoids increase gluconeogenesis and antagonize insulin for an overall hyperglycemic effect. Appetite is stimulated by the steroid-induced euphoria. Continued use of glucocorticoids has catabolic effects because skeletal muscle and collagen proteins are broken down to provide the precursors for gluconeogenesis.
When used as anxiolytics, the benzodiazepines (BZD) became well known for their appetite stimulation effects independent of their anxiolytic activity. Stereospecific binding of a BZD to GABA A receptors in the parabrachial nucleus produces a strong dose-dependent (ie, voracious) increase in food consumption. Hunger level and degree of satiety has no effect on BZD-induced food intake. So, it appears that the BZDs do not modulate hunger or satiety directly but act specifically to enhance taste and other sensory characteristics of food. By manipulating the stereospecificity of the BZD drugs, appetite-selective partial agonist compounds have been developed that have actions disassociated from the other major effects of full agonists (eg, amnesia, sedation, incoordination, anxiolysis). Likewise, inverse agonists of the BZD receptors reduce food consumption. BZD receptor antagonists block the appetite-simulating effects of the full or partial agonists, as well as the appetite-suppressive effects of the inverse agonists. So, there is a bidirectional control of food intake mediated by a common subset of BZD receptors. Levels of food intake, ranging from voracious consumption at one extreme to complete anorexia at the other, with every level in between, can be achieved by the relative concentration of agonists and inverse agonists binding to those BZD receptors specifically involved in the control of appetite. Diazepam is an appetite stimulant when administered IV to cats. If responsive, cats begin eating within a few seconds of IV administration, so palatable food should be available before injection. Oxazepam, a metabolite of diazepam, can be given orally to cats. Diazepam is the more effective appetite stimulant but also causes a greater sedative effect than oxazepam.
Cyproheptadine is an antihistamine with serotonin-antagonist action used clinically in cats as an appetite stimulant. It acts as a 5-HT2 receptor antagonist. The lateral hypothalamus normally excretes endogenous opiates, which stimulate eating. The release of these endogenous opiates is inhibited by serotonin and cholecystokinin release, thus inhibiting eating. Cats are very sensitive to changes in serotonin concentrations, so serotonin antagonists are very potent in cats. CNS excitement and aggressive behavior may occur in some cats.
Mirtazapine is an antidepressant used to treat moderate to severe depression in people. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor (SSRIs such as fluoxetine are noted to decrease appetite). It is an antagonist of presynaptic α2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5-HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and SSRIs. Because of its unique pharmacologic profile, mirtazapine usually does not cause anticholinergic effects, serotonin-related adverse effects, or adrenergic adverse effects (orthostatic hypotension and sexual dysfunction). Antihistaminic drowsiness is a common effect. Mirtazapine is used for disease conditions in which inappetance and nausea go together, such as in the treatment of GI disease or liver or kidney disease. Mirtazapine can also be used to alleviate the nausea and appetite loss that accompanies chemotherapy. α-Adrenergic receptors in the chemoreceptor trigger zone are important in inducing emesis in cats. Clinically, mirtazapine is an effective appetite stimulant and antiemetic for cats with chronic kidney disease and appears to be a useful adjunct in nutritional management of these cats. There is little pharmacokinetic information on mirtazapine in dogs and cats, but mirtazapine shows sexual effects in hepatic metabolism in people, so it is likely there is similar variation in metabolism in dogs and cats and the potential for variation in efficacy.
Mirtazapine is typically given once a day to dogs and twice a week to cats. It should be used with caution in dogs and cats with severe liver or kidney disease, because mirtazapine clearance will be reduced. In cats and small dogs, it is difficult to reduce the dose, because the smallest tablet manufactured cannot be accurately cut much smaller than the regular dosing schedule allows. In this situation, a compounding pharmacy could be employed to create a lower dose, or the dosing schedule can be extended. This is especially important for cats with liver disease.
Megestrol acetate is a synthetic progestin. It has significant antiestrogen and glucocorticoid activity, with resulting adrenal suppression. It is used to stimulate appetite and promote weight gain in people with cancer and cachexia (related to acquired immunodeficiency syndrome) and may have a similar effect in anorectic cats and dogs. Megestrol acetate is contraindicated in pregnant animals and in animals with uterine disease, diabetes mellitus, or mammary neoplasia. In cats, megestrol acetate can induce a profound adrenocortical suppression, adrenal atrophy, and diabetes mellitus, which may or may not be reversible. Toxicity is less of a problem in dogs.
Other drugs used as appetite stimulants include B vitamins and glucocorticoids. B vitamin preparations are administered orally and parenterally to debilitated animals, especially horses, to promote appetite. Glucocorticoids increase gluconeogenesis and antagonize insulin for an overall hyperglycemic effect. Appetite is stimulated by the steroid-induced euphoria. Continued use of glucocorticoids results in catabolic effects, as skeletal muscle and collage proteins are broken down to provide the precursors for gluconeogenesis.