INTRODUCTION

The use of antidepressants in small animals for a number of disorders including inappropriate urination or incontinence, neuropathic pain, urinary tract obstruction, and separation anxiety is growing, and thus the incidence of accidental overdose has also increased. Between 1998 and 2000, the American Society for the Prevention of Cruelty to Animals’ Animal Poison Control Center received more than 1075 reports of accidental antidepressant drug ingestion.¹

One of the most common types of antidepressants prescribed for companion animals is the cyclic antidepressant (CA), which consists of multiple-ring aromatic nuclei and an aliphatic aminopropyl side chain. CAs can be divided into subclasses based on the number of rings. Box 89-1 shows a list of CAs grouped by the number of rings. The most common of these drugs used in veterinary medicine are the tricyclic antidepressants (TCAs) amitriptyline (Elavil, AstraZeneca), imipramine (Tofranil, Novartis), and clomipramine (Clomicalm, Novartis). Although newer antidepressants that have a wider margin of safety and are less likely to cause severe side effects in people are available, such as the selective serotonin reuptake inhibitors and reversible monoamine oxidase-A inhibitors, CAs are still widely prescribed in people. A recent study of antidepressant poisonings in people showed that 43% were due to CAs,² and the most recent survey of toxicities reported to American poison control centers showed that antidepressants were the second most common class of drug responsible for fatalities, with amitriptyline being the most common agent involved.³ These data suggest that companion animals are at risk of exposure from both veterinary and human products.

The CAs are thought to exert their therapeutic effects in the central nervous system via inhibition of presynaptic amine pumps responsible for reuptake of norepinephrine and serotonin, resulting in an increased concentration of these neurotransmitters in the synaptic cleft. Organic depression is thought to be mediated, at least in part, by deficits in the concentrations of these neurotransmitters. In addition to these therapeutic effects, CAs also cause sedation, have both peripheral and central anticholinergic effects (via blocking of muscarinic receptors), cause α₁-adrenergic blockade, and are antagonists at histamine receptors (H₁ and H₂).⁴

PHARMACOKINETICS

The pharmacokinetic profiles of the CAs are highly variable, both among drugs and among individuals. However, there are some common characteristics. All of the drugs are absorbed rapidly from the gastrointestinal (GI) tract, as well as from parenteral injection. Peak plasma concentrations occur within 1 to 12 hours. Plasma half-life is variable and depends on the specific drug (Table 89-1), but ranges from 2 to 32 hours for the most common veterinary CAs. They are highly lipophilic, cross the blood-brain barrier, and are extensively protein bound. They cross the placenta and are present in the milk in comparable or higher concentrations than in the serum. CAs are metabolized in the liver, and some of the metabolites are biologically active. Most of the drugs undergo enterohepatic recirculation, with excretion occurring predominantly via the urine, and to a lesser extent in the feces.¹

Table 89-1 Therapeutic Doses, Toxic Doses, and Pharmacokinetics of Common Tricyclic Antidepressants

CLINICAL SIGNS

Clinical signs of CA overdose are due to both central and peripheral effects, and can become apparent within 30 minutes of ingestion because of rapid absorption. Progression can occur quickly, with death occurring within 1 to 2 hours without intervention.⁵ The main clinical signs of CA overdose are due to CNS disturbances from anticholinergic effects and elevations of norepinephrine and serotonin concentrations, and cardiovascular disturbances from peripheral anticholinergic effects, α-adrenergic blockade, and blocking of sodium channels in cardiac tissue.

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