Also see Overview of Systemic Pharmacotherapeutics of the Nervous System.
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,
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
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
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,
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.
Miscellaneous (Atypical) Antidepressants
These antidepressants have nonselective
receptor-blocking effects and are used when selective serotonin reuptake
inhibitors or tricyclic antidepressants have not been effective. Examples
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
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
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
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
The most commonly used phenothiazines in veterinary
medicine are acepromazine, chlorpromazine, and
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
Last full review/revision August 2014 by Safdar A. Khan, DVM, MS, PhD, DABVT