Tranquilizers, Antidepressants, Sleep Aids, and Anticonvulsants (Toxicity)
Benzodiazepines bind γ-aminobutyric acid (inhibitory neurotransmitter) receptors and are used for seizure control and as anxiolytics. Whereas diazepam is probably best known in the veterinary field, alprazolam, chlordiazepoxide, clonazepam, lorazepam, oxazepam, and triazolam are all commonly prescribed medications. In general, all are rapidly and fairly completely absorbed, lipophilic, and highly protein bound. Metabolism is mostly by glucuronidation, so cats may be more sensitive to adverse effects. Several have active metabolites (eg, diazepam, clorazepate) and consequently have much longer duration of signs.
The most common signs seen, at a wide range of dosages, are CNS depression, respiratory depression, ataxia, weakness, disorientation, nausea, and vomiting. Some animals, especially at high doses, may show CNS excitation instead of depression (paradoxical reaction), which may be followed by CNS depression. Other common signs are hypothermia, hypotension, tachycardia, muscle hypotonia, and meiosis. Some cats develop signs of acute, potentially fatal hepatic failure after repeated oral administration of diazepam for several days.
Emesis can be induced if ingestion is recent and no clinical signs are present. Gastric lavage, followed by administration of activated charcoal, can be performed if the ingested amount is very high. The animal should be kept warm and quiet and closely monitored for responsiveness to stimuli and adequate breathing. IV fluids will help support blood pressure. If the affected animal is recumbent and severe respiratory depression has developed, the reversal agent flumazenil can be given at a dosage of 0.01 mg/kg, slow IV, in both cats and dogs. Flumazenil has a short half-life, so it may need to be repeated. Benzodiazepines should not be used to control CNS excitation, because a paradoxical reaction may occur. In such situations, low doses of acepromazine or barbiturates may be useful to control initial CNS excitation.
Antidepressants fall into several classes. An overdose of almost any of them can result in development of serotonin syndrome (see Serotonin Syndrome).
Selective serotonin reuptake inhibitors (SSRIs) include sertraline, fluoxetine, paroxetine, and fluvoxamine. They block the activity of serotonin receptors at presynaptic membranes and have little effect on other neurotransmitters. In veterinary medicine, these SSRIs are sometimes used to control aggression, obsessive-compulsive disorder, separation anxiety, pruritus, and inappropriate elimination in dogs and cats. Overdosage of SSRIs in dogs and cats is manifested by vomiting, lethargy, mydriasis, ataxia, shaking, seizures, hyperactivity, tachycardia or bradycardia, and vocalization (see Serotonin Syndrome).
Tricyclic antidepressants (eg, amitriptyline, clomipramine, nortriptyline) are commonly used psychoactive agents. They are structurally similar to the phenothiazines, with similar anticholinergic, adrenergic, and α-blocking properties. After absorption, these agents are extensively bound to plasma proteins and also bind to tissue and cellular sites, including the mitochondria. Cyclic antidepressants block the amine pump and stop neuronal reuptake of norepinephrine, serotonin, and dopamine. These agents also appear to have a slight α-adrenergic blocking effect. Tricyclics may exert their major toxicity via a nonspecific membrane-stabilizing effect, similar to chlorpromazine and the β blockers. Tricyclics also have central and peripheral anticholinergic activity, along with antihistaminic effects. Clinical signs of toxicosis include CNS stimulation (agitation, confusion, pyrexia), cardiac arrhythmias, hypertension, myoclonus, nystagmus, seizures, metabolic acidosis, urinary retention, dry mouth, mydriasis, and constipation. This may be followed by CNS depression (lethargy), ataxia, hypothermia, respiratory depression, cyanosis, hypotension, and coma.
Monoamine oxidase inhibitors are antidepressants used mainly to treat atypical depression in people. In dogs, selegiline, a monoamine oxidase-B inhibitor, is used to treat Cushing disease and cognitive dysfunction (canine dementia). Selegiline is absorbed rapidly orally. Metabolites of selegiline include amphetamine and methamphetamine. Its half-life in dogs is ~1 hr.
Emesis should be induced in cases of recent exposure if the animal is asymptomatic. This can be followed by activated charcoal (even several hours after ingestion) plus a cathartic such as sorbitol or sodium sulfate (magnesium sulfate is contraindicated, because it can add to CNS depression). Diazepam can be given to control seizures. Serotonin syndrome signs should be managed as needed. Heart rate and rhythm should be monitored, and cardiac arrhythmias treated. Atropine should not be used to control bradycardia, because it can aggravate anticholinergic effects of tricyclic antidepressants.
This group of clinical signs usually includes three of the following features: altered mental status, agitation, nervousness, myoclonus, hyperreflexia, tremors, diarrhea, incoordination, cardiovascular changes (heart rate and blood pressure), and fever. It often occurs because of repeated use or overdose or ingestion of substances that result in increased free levels of serotonin, such as antidepressants or profound stimulants (eg, amphetamines). Cyproheptadine is a serotonin antagonist often used for treatment. It is available only as a tablet but can be dissolved in a small amount of saline and administered per rectum at 1.1 mg/kg in dogs or 2 mg/dose in cats. If there is a good response to the initial dose, it can be repeated only if signs recur. Phenothiazines such as acepromazine or chlorpromazine also have antiserotonergic effects and can be used to control hyperactivity. Benzodiazepines such as diazepam can be used to control CNS effects. β blockers such as propranolol (0.02–0.04 mg/kg, IV) can be used to control tachycardia. Other treatment measures may include induction of emesis in asymptomatic animals within 2 hr of exposure, followed by administration of activated charcoal and IV fluids.
Both long-acting and short-acting barbiturates may be encountered. The long-acting group includes phenobarbital, mephobarbital, and primidone—all commonly used as anticonvulsants or sedatives. The short-acting (butabarbital, pentobarbital, secobarbital) and ultra short-acting (thiamylal and thiopental) barbiturates are used mainly for induction of anesthesia and seizure control. All are readily absorbed from the gut and have extensive liver metabolism; metabolites are primarily excreted via the kidneys. The onset of clinical signs varies from 15 min to several hours, and duration can be up to several days for the long-acting class. The most common signs are sedation, ataxia, respiratory depression, coma, loss of reflexes, hypotension, and hypothermia.
Management is aimed at life support while attempting to remove unmetabolized drug from the body. Emesis should be induced if the exposure is very recent and the animal is asymptomatic. Gastric lavage while protecting the airway can remove much of the drug still in the stomach. Activated charcoal readily adsorbs barbiturates; small doses repeated every 4–6 hr can further decrease the body burden, even if overdose has resulted from use of an injectable product. IV fluids can be given to support blood pressure. Respiratory effort and effectiveness needs to be closely monitored; treatment may require positive-pressure ventilation or oxygen. Doxapram (1–5 mg/kg, slow IV in dogs, and 5–10 mg/cat) may help to stimulate respiration. Support to maintain body temperature may be necessary. Comatose animals should be intubated with a cuffed endotracheal tube, because aspiration is a common complication. Depending on the dose, aggressive supportive treatment may be necessary for 1–3 days.
Zolpidem, zaleplon, and eszopiclone are drugs used as sleep aids and have a mechanism of action similar to that of the benzodiazepines. These agents have a very rapid onset (usually <30 min) and a similarly short half-life. While the expected result from ingestion would be marked sedation, paradoxical excitement also occurs. Dosages as low as 0.22 mg/kg have resulted in sedation and ataxia, and dogs have developed tremors, vocalizing, and pacing at dosages as low as 0.6 mg/kg.
GI decontamination can be performed if the ingestion was recent and no signs are seen. For mild signs, keeping the pet quiet and in a safe place may suffice. If paradoxical excitement develops, symptomatic treatment should be given and will vary with the signs and their intensity. Hyperexcitation may be controlled with low doses of acepromazine or other phenothiazines. Use of diazepam may aggravate signs of CNS depression. Flumazenil (0.01 mg/kg, IV) can be used if clinical signs of toxicosis are severe.
The most commonly used phenothiazines in veterinary medicine are acepromazine, chlorpromazine, and promazine. In domestic animals, they are used as tranquilizers, preanesthetic agents, antiemetics, and for treatment of CNS agitation after specific drug overdoses (amphetamines, cocaine). The most common signs of overdose are sedation, weakness, ataxia, collapse, behavioral changes, hypothermia, hypotension, tachycardia, and bradycardia.
Treatment consists of symptomatic and supportive care. Because of the rapid onset of CNS signs, emesis should only be attempted in a recent exposure and should be followed by administration of activated charcoal and a cathartic. Repeated doses of activated charcoal may be helpful, especially for large ingestions. Hypotension should be treated with IV fluids. Dopamine may be used if fluid administration does not correct hypotension. Body temperature, heart rate, and blood pressure should be monitored and treated symptomatically.