14 Lynne Seibert1 and Sharon Crowell‐Davis2 1 Veterinary Behavior Consultants, Roswell, GA, USA 2 University of Georgia, Athens, GA, USA Antipsychotics are used to treat most forms of psychosis, including schizophrenia, in humans. They do not have the same significance in animal behavior therapy and are usually most appropriately used on a short‐term, intermittent basis. The first antipsychotic, chlorpromazine, was developed in 1950. Individual antipsychotic drugs show a wide range of physiological effects, resulting in tremendous variation in side effects. The most consistent pharmacological effect is an affinity for dopamine receptors. In humans, antipsychotics produce a state of relative indifference to stressful situations. In animals, antipsychotics reduce responsiveness to a variety of stimuli, exploratory behavior, and feeding behavior. Conditioned avoidance responses are lost in animals that are given antipsychotics. Antipsychotic agents are divided into two groups based on side effect profiles (low‐potency and high‐potency drugs) or by structural classes (Table 14.1). Low‐potency antipsychotics have a lower affinity at D2 receptor sites, higher incidence of anticholinergic effects (sedation), stronger α‐adrenergic blockade (cardiovascular side effects), and require larger doses (1–3 mg kg−1), but have a lower incidence of extrapyramidal side effects. High‐potency antipsychotics show a greater affinity for D2 receptor sites, have fewer autonomic effects, less cardiac toxicity, a higher incidence of extrapyramidal signs, and are effective in smaller doses (0.5–1 mg kg−1) (Simpson and Simpson 1996). The phenothiazine neuroleptics are antipsychotics that are commonly used in veterinary medicine for sedation and restraint. Table 14.1 Classes of antipsychotic drugs. Antipsychotic agents block the action of dopamine, a catecholamine neurotransmitter that is synthesized from dietary tyrosine. Dopamine regulates motor activities and appetitive behaviors. Dopamine depletion is associated with behavioral quieting, depression, and extrapyramidal signs. Excess dopamine is associated with psychotic symptoms and the development of stereotypies. A large proportion of the brain’s dopamine is located in the corpus striatum and mediates the part of the extrapyramidal system concerned with coordinated motor activities. Dopaminergic neurons project to the basal ganglia and extrapyramidal neuronal system. Side effects associated with blockade of this system are called extrapyramidal responses. Dopamine is also high in some regions of the limbic system (Marder and Van Putten 1995). The nigrostriatal pathway consists of cell bodies originating in the substantia nigra and mediates motor activities. The mesolimbic pathway consists of neuronal cell bodies that originate in the ventral tegmental area, project to ventral striatum and limbic structures, and mediate appetitive behaviors. Dopamine is broken down by monoamine oxidase inside the presynaptic neuron or by catechol‐O‐methyltransferase outside the presynaptic neuron. There are five dopamine receptor subtypes. Traditional antipsychotics are D2 receptor antagonists and block 70–90% of D2 receptors at therapeutic doses. Antipsychotics have a wide spectrum of physiological actions. Traditional antipsychotics have antihistaminic activity, dopamine receptor antagonism, α‐adrenergic blockade, and muscarinic cholinergic blockade. Blocking the dopamine receptors in the basal ganglia and limbic system produces behavioral quieting, as well as depression of the reticular‐activating system and brain regions that control thermoregulation, basal metabolic rate, emesis, vasomotor tone, and hormonal balance. Antipsychotics produce ataraxia: a state of decreased emotional arousal and relative indifference to stressful situations. They suppress spontaneous movements without affecting spinal and pain reflexes. Antipsychotic agents are most often used in veterinary practice when chemical restraint is necessary. Antipsychotic agents are used for restraint or the temporary decrease of motor activity in cases of intense fear or stereotypic behavior. A complete behavioral and medical history is necessary to determine which pharmacological agents will be the most beneficial for any given case. A comprehensive treatment plan that includes behavior modification exercises and environmental modifications, along with drug therapy, has the best chance for success (Overall 1997). Antipsychotic agents have poor anxiolytic properties and should not be the sole treatment for any anxiety‐related disorder. Therefore, while they can be useful in preventing self‐injury or damage to the environment by an animal exhibiting a high‐ intensity fear response, they are not appropriate for long‐term therapy and treatment of phobias. Antipsychotic agents are indicated for the treatment of intense fear responses requiring heavy sedation to prevent self‐injury or property damage. Sedation to the point of ataxia may be necessary to control frantic responses in storm‐phobic dogs, but owners often report that their dogs still appear to be frightened. Antipsychotic agents have also been used in game capture operations and to allow physical examination in intractable animals. Antipsychotics can also be used as antiemetics and for the treatment and prevention of motion sickness. When used as preanesthetic agents, antipsychotics may induce a state of indifference to a stressful situation. Antipsychotic agents produce inconsistent results for the treatment of aggressive behavior, and in some cases have induced aggressive behavior in animals with no history of aggressiveness (Overall 1997). Antipsychotic agents have a high hepatic extraction ratio. Metabolites are generally inactive compounds and excreted in the urine. Maximal effect occurs about one hour after administration. Duration of action ranges from 4 to 24 hours. Half‐lives range from 10 to 30 hours in humans. These agents are highly lipid soluble and highly protein bound. Significant side effects can occur with acute antipsychotic use because of decreased dopaminergic activity in the substantia nigra. Side effects may include motor deficits or Parkinsonian‐like symptoms, such as difficulty initiating movements (akinesis), muscle spasms (dystonia), motor restlessness (akathisia), and increased muscle tone resulting in tremors or stiffness. Behavior effects include indifference (ataraxia), decreased emotional reactivity, and decreased conditioned avoidance responses. Antipsychotic agents may also cause a suppression of spontaneous movements, a decrease in apomorphine‐induced stereotypies, a decrease in social and exploratory behaviors, a decrease in operant responding, and a decrease in responses to non‐nociceptive stimuli. Tardive dyskinesia occurs as a result of the upregulation of dopamine receptors with chronic antipsychotic use. An increase in postsynaptic receptor density due to dopamine blockade can result in the inability to control movements or torticollis, and hyperkinesis. The dopaminergic system is unique in that intermittent use of antipsychotic medications can result in the upregulation of postsynaptic receptors. Chronic side effects may occur after three months of treatment. At least 10–20% of human patients treated with antipsychotics for more than one year develop tardive dyskinesia, and the symptoms are potentially irreversible even after the medication is discontinued. Bradycardia and transient hypotension due to α‐adrenergic blocking effects can occur. Syncope has been reported, particularly in brachycephalic breeds. Hypertension is possible with chronic use. Endocrine effects include an increase in serum prolactin, the luteinizing hormone, follicle‐stimulating hormone suppression, gynecomastia, gallactorhea, infertility, and weight gain. Parasympatholytic autonomic reactions are possible. Other side effects include lowered seizure threshold, hematological disorders (thrombocytopenia), hyperglycemia, and electrocardiographic changes. Priapism has been reported in stallions. Antipsychotic agents should be used with caution, if at all, in patients with seizure disorders, hepatic dysfunction, renal impairment, or cardiac disease, and in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers. Neuroleptic malignant syndrome is a rare, but potentially fatal, complex of symptoms associated with antipsychotic use. It results in muscular rigidity, autonomic instability, hyperthermia, tachycardia, cardiac dysrhythmias, altered consciousness, coma, increased liver enzymes, creatine phosphokinase, and leukocytosis. Mortality reaches 20–30% in affected humans. Treatment includes discontinuation of the antipsychotic medication, symptomatic treatment, and medical monitoring. Antipsychotic agents will typically have an immediate effect on behavior and so do not require chronic dosing, but can be used as needed for their behavioral quieting effects. When used intermittently, antipsychotic agents do not need to be gradually withdrawn. An owner consent form is helpful to outline potential adverse events and ensure that the owner is aware of these. Acepromazine is a low‐potency phenothiazine neuroleptic agent that blocks postsynaptic dopamine receptors and increases the turnover rate of dopamine. Acepromazine has a depressant effect on the central nervous system (CNS) resulting in sedation, muscle relaxation, and a reduction in spontaneous activity. In addition, there are anticholinergic, antihistaminic, and α‐adrenergic blocking effects. Acepromazine, like other phenothiazine derivatives, is metabolized in the liver. Both conjugated and unconjugated metabolites are excreted in the urine. Metabolites can be found in the urine of horses up to 96 hours after dosing. Horses should not be ridden within 36 hours of treatment. Acepromazine is indicated as a preanesthetic agent, for control of intractable animals, as an antiemetic agent to control vomiting due to motion sickness in dogs and cats, and as a tranquilizer in horses. Acepromazine can produce prolonged depression when given in excessive amounts or when given to animals that are sensitive to the drug. The effects of acepromazine may be additive when used in combination with other tranquilizers and will potentiate general anesthesia. Tranquilizers should be administered in smaller doses during general anesthesia and to animals that are debilitated, animals with cardiac disease, or animals with sympathetic blockage, hypovolemia, or shock. Phenothiazines should be used with caution during epidural anesthetic procedures because they may potentiate the hypotensive effects of local anesthetics. Phenothiazines should not be used prior to myelography. Acepromazine should not be used in patients with a history of seizures and should be used with caution in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers. Studies in rodents have demonstrated the potential for embryotoxicity. Phenothiazines should not be used in patients with bone marrow depression. Phenothiazines depress the reticular activating system and brain regions that control vasomotor tone, basal metabolic rate, and hormonal balance. They also affect extrapyramidal motor pathways and can produce muscle tremors and akathisia (restlessness, pacing, and agitation). Cardiovascular side effects include hypotension, bradycardia, cardiovascular collapse, and reflex tachycardia. Hypertension is possible with chronic use. Syncope, collapse, apnea, and unconsciousness have been reported. Other side effects include hypothermia, ataxia, hyperglycemia, excessive sedation, and aggression. Paradoxical excitability has been reported in horses, cats, and dogs. Hematological disorders have been reported in human patients taking phenothiazines, including agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenia, and pancytopenia. There is anecdotal evidence that chronic use may result in the exacerbation of noise‐related phobias. Startle reactions to noise can increase with acepromazine use. Acepromazine is contraindicated in aggressive dogs, because it has been reported to facilitate acute aggressiveness in rare cases. Priapism, or penile prolapse, may occur in male large animals. Acepromazine should be used with caution in stallions, as permanent paralysis of the retractor muscle is possible. In a safety study, no adverse reactions to acepromazine occurred when it was administered to dogs at three times the upper limit of the recommended daily dosage (1.5 mg lb−1). This dose caused mild depression that resolved within 24 hours after termination of dosing. The LD50 (the dose that kills half of the animals [mice] tested) is 61 mg kg−1 for intravenous administration and 257 mg kg−1 for oral administration. Additive depressant effects can occur if acepromazine is used in combination with anesthetics, barbiturates, and narcotic agents. Concurrent use of propranolol can increase blood levels of both drugs. Concurrent use of thiazide diuretics may potentiate hypotension. Gradually increasing doses of up to 220 mg kg−1 PO were not fatal in dogs, but resulted in pulmonary edema. Hypotension can occur after rapid intravenous injection causing cardiovascular collapse. Epinephrine is contraindicated for the treatment of acute hypotension produced by phenothiazine tranquilizers because further depression of blood pressure can occur. Overdosage of phenothiazine antipsychotics in human patients is characterized by severe CNS depression, coma, hypotension, extrapyramidal symptoms, agitation, convulsions, fever, dry mouth, ileus, and cardiac arrhythmias. Treatment is supportive and symptomatic, and it may include gastric lavage, airway support, and cardiovascular support. Dosages should be individualized depending upon the degree of tranquilization required. Generally, as the weight of the animals increases, the dosage requirement in terms of milligram of medication per kilogram weight of the animal decreases. Doses that are 10 times lower than the manufacturer’s recommended dose may be effective. Arousal is most likely in the first 30 minutes after dosing. Maximal effects are generally reached in 15–60 minutes, and the duration of effect is approximately 3–7 hours. There may be large individual variation in response (Table 14.2 and Table 14.3). Table 14.2 Doses for antipsychotics for dogs and cats. prn, according to need. Table 14.3 Doses of antipsychotics for horses.
Antipsychotics
Introduction
Phenothiazine tranquilizers
High potency
Fluphenazine (Prolixin)
Low potency
Acepromazine (Promace)
Chlorpromazine (Thorazine)
Promazine (Sparine)
Thioridizine (Melleril)
Butyrophenones
Haloperidol (Haldol)
Droperidol (Innovar)
Azaperone (Stresnil, Suicalm)
Diphenylbutylpiperidines
Pimozide (Orap)
Dibenzoxazepines
Clozapine (Clozaril)
Atypical antipsychotics
Sulpiride (Sulpital)
Action
Overview of Indications
General Pharmacokinetics
Contraindications, Side Effects, and Adverse Events
Overdose
Clinical Guidelines
Specific Medications
I. Acepromazine Maleate
Clinical Pharmacology
Indications
Contraindications
Side Effects
Adverse Drug Interactions
Overdose
Doses in Nonhuman Animals
Drug
Dogs
Cats
Acepromazine
0.5–2.0 mg kg−1 PO q8h or prn
1.0–2.0 mg kg−1 PO prn
Chlorpromazine
0.8–3.3 mg kg−1 PO q6h
3.0–6.0 mg kg−1 PO
Promazine
2.0–6.0 mg kg−1 IM or IV q4–6h prn
2.0–4.5 mg kg−1 IM
Thioridizine
1.0–3.0 mg kg−1 PO q12–24h
Haloperidol
0.05–2.0 mg kg−1 PO q12h
0.1–1.0 mg kg−1 PO
Pimozide
0.03–0.3 mg kg−1 PO
Clozapine
1.0–70 mg kg−1 PO
Sulpiride
5.0–10.0 mg kg−1 PO
Drug
Dose
Acepromazine
0.02–0.1 mg kg−1 IM
Promazine
0.4–1.0 mg kg−1 IV or 1.0–2.0 mg kg−1 PO q4–6h
Haloperidol decanoate
0.004 mg kg−1 IM
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