Appetite disorders are common in veterinary patients.
Obesity from overfeeding is common in companion animals and is best managed by educating the owner and regulating the patient's diet.
Anorexia is a common clinical sign of many systemic diseases, exacerbating disease-induced catabolism. In an anorectic patient that does not respond to coaxing with small quantities of highly palatable foods, drug treatment may be used to stimulate appetite.
Specific drugs can influence food intake by affecting hunger, satiety, or the positive evaluation of taste. If drug treatment is unsuccessful, more invasive procedures, such as nasogastric or gastrotomy tube feeding, or total parenteral nutrition may be necessary.
Appetite Suppression in Monogastric Animals
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 action as a weight loss drug is not completely understood; however, dirlotapide appears to decrease 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 loss effect.
Dirlotapide is available systemically, but absorption in dogs is highly variable. Absorbed dirlotapide is metabolized in the liver; the 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 do seem to correlate with systemic toxicity.
Dirlotapide should not be used in cats. It increases the risk of hepatic lipidosis during weight loss in obese cats.
In humans, adverse reactions associated with ingesting dirlotapide included abdominal distention, abdominal pain, diarrhea, flatulence, headache, increased serum transaminases, nausea, and vomiting.
Dirlotapide is no longer available as an approved product for dogs.
Appetite Stimulation in Monogastric Animals
Anabolic steroids are synthetic derivatives of testosterone that have enhanced anabolic effects with decreased androgenic effects. Anabolic steroids do not directly affect hunger, satiety, or the 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 and calorie intake and treatment of underlying disease.
Anabolic steroids stimulate hematopoiesis, appetite, and weight gain. Adverse effects of anabolic steroid treatment include hepatotoxicosis, masculinization, and early closure of bony epiphyses in young animals. Anabolic steroids are contraindicated in animals with congestive heart failure because they promote sodium and water retention.
Because of human abuse potential, anabolic steroids are controlled substances. Once infamous for abuse in humans and horses, stanozolol and boldenone undecylenate are no longer marketed by veterinary pharmaceutical companies in North America. Currently, anabolic products for veterinary use can be obtained only from a compounding pharmacy. Use of anabolic steroids in performance horses is prohibited by most equine sport organizations.
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.
Megestrol acetate is a synthetic progestin. It has noteworthy antiestrogen and glucocorticoid activity, with resulting adrenal suppression. It is used to stimulate appetite and promote weight gain in humans with cancer and cachexia and may have a similar effect in anorectic cats and dogs.
Megestrol acetate is contraindicated in pregnant patients and in patients with uterine disease, diabetes mellitus, or mammary neoplasia. In cats, megestrol acetate can induce profound adrenocortical suppression, adrenal atrophy, and diabetes mellitus, which may or may not be reversible. Toxic effects are less of a problem in dogs.
Benzodiazepines are well known for their appetite stimulation effects independent of their anxiolytic activity. Stereospecific binding of a benzodiazepine to GABAA receptors in the parabrachial nucleus produces a strong dose-dependent increase in food consumption. The amount of hunger and extent of satiety have no effect on benzodiazepine-induced food intake. Therefore, it appears that benzodiazepines do not modulate hunger or satiety directly but act specifically to enhance taste and other sensory characteristics of food.
Through manipulation of the stereospecificity of benzodiazepines, appetite-selective partial agonist compounds have been developed that have actions dissociated from the other major effects of full agonists (eg, amnesia, sedation, incoordination, anxiolysis). Likewise, inverse agonists of benzodiazepinergic receptors decrease food consumption. Benzodiazepinergic 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, bidirectional control of food intake is mediated by a common subset of benzodiazepinergic receptors. Specific amounts of food intake, ranging from voracious consumption at one extreme to complete anorexia at the other—with every variation in between—can be achieved by binding of the relative concentrations of agonists and inverse agonists to benzodiazepinergic 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 receiving the drug, so palatable food should be available before injection.
Orally administered diazepam (both brand-name and generic formulations) has been associated with fulminant hepatic necrosis in cats. Initial clinical signs include lethargy, ataxia, and anorexia that occur as early as 5 days after oral diazepam administration, and there is a high case fatality rate. If diazepam is administered orally in cats, liver enzymes should be checked before treatment is initiated and again 5 days later. If liver enzymes are elevated, diazepam treatment should immediately be suspended and supportive care instituted.
Oxazepam, a metabolite of diazepam, can be administered orally to cats and appears safe.
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 sensitive to changes in serotonin concentrations, so serotonergic receptor antagonists are very potent in cats.
Cyproheptadine may decrease the seizure threshold, increase the severity of seizures, and decrease the efficacy of anticonvulsant drugs. In some cats, CNS excitement and aggressive behavior may occur.
Mirtazapine is an antidepressant used to treat moderate to severe depression in humans. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor (selective serotonin reuptake inhibitors [SSRIs] such as fluoxetine are noted to decrease appetite). It is an antagonist of presynaptic alpha-2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin presynaptic axons; alpha-adrenergic receptors in the chemoreceptor trigger zone (CRTZ) are important for inducing emesis in cats. Mirtazapine is also a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors. This mechanism of action maintains equivalent antidepressant efficacy; however, it minimizes many of the adverse effects common to both tricyclic antidepressants and SSRIs.
Because of its unique pharmacological profile, mirtazapine usually does not have 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 both inappetance and nausea, 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 accompany chemotherapy.
Clinically, orally administered mirtazapine is an effective appetite stimulant and antiemetic for cats with chronic kidney disease, and it appears to be a useful adjunct in the nutritional management of these cats.
Little pharmacokinetic information on mirtazapine in dogs and cats is available; however, in humans, hepatic metabolism of mirtazapine is affected by sex, so it is likely there is similar variation in metabolism in dogs and cats, along with the potential for variation in efficacy. Oral dosing for mirtazapine is typically once a day for dogs and twice a week for cats.
In the US, an approved transdermal mirtazapine product for cats is available. The absorption and effectiveness of the approved product has been demonstrated. In contrast, like many compounded transdermal drugs, the absorption and bioavailability of compounded transdermal mirtazapine are often unknown and may be inadequate or variable, making treatment outcomes unpredictable. The transdermal formulation of mirtazapine (2 mg/cat, applied topically to the inner side of the pinna, every 24 hours for 14 days) has been shown to be effective for the management of appetite stimulation in cats. Transdermal mirtazapine should not be administered in combination with or within 14 days before or after treatment with monoamine oxidase inhibitors (eg, selegiline, amitraz) because the risk of serotonin syndrome may be higher. The most common adverse effects include application site reactions (erythema, dermatitis or irritation, residue, crust or scabs), behavioral abnormalities (vocalization and hyperactivity), and vomiting.
Mirtazapine should be used with caution in dogs and cats with severe liver or kidney disease because, in these cases, hepatic clearance is decreased and the elimination half-life is prolonged. In cats and small dogs, it is difficult to decrease the dose because the smallest tablet manufactured cannot be accurately cut small enough. At doses of 3.75 mg/cat or higher, cats develop adverse effects associated with serotonin syndrome at higher rates.
Capromorelin is an orally active small-molecule growth hormone secretagogue (GHS) that is a potent and selective ghrelin receptor agonist. As a ghrelin receptor agonist, capromorelin stimulates appetite and increases body weight in dogs with inappetance from many causes.
In clinical trials, capromorelin was well tolerated, with vomiting and diarrhea reported as the most common adverse effects. Polydipsia and hypersalivation are also reported. Capromorelin is approved for dogs in the US, and its safety data are robust enough that capromorelin has no treatment duration, age, or weight restrictions. Capromorelin also appears safe and effective in cats.
Other drugs used as appetite stimulants include B vitamins.
There is increasing interest in using cannabinoids (cannabidiol [CBD] and tetrahydrocannabinol [THC]) in dogs and cats to stimulate appetite; so far, however, evidence of efficacy is limited. The effects of CBD on food intake have been inconclusive in both human and animal studies. Some human cancer patients treated with CBD report that it improves appetite and makes food taste better.