15 Sharon L. Crowell‐Davis University of Georgia, Athens, GA, USA Central nervous system (CNS) stimulants increase synaptic dopamine and norepinephrine. CNS stimulants are used to treat attention deficit disorder (ADD), also called attention deficit hyperactivity disorder (ADHD), or hyperkinesis in dogs (Corson et al. 1976). While CNS stimulants may decrease overall activity in animals with true hyperkinesis, the effects that give the medications their names will occur in animals that do not have true hyperkinesis. Therefore, during a testing situation, preparations should be made for this possibility. A variety of other side effects can occur in animals with and without hyperkinesis. These include pain and difficulty with urination due to contraction of the urethral sphincter, gastrointestinal disturbance, decreased appetite, anorexia, dry mouth, convulsions, hyperthermia, increased blood pressure, tachycardia, and cardiac arrhythmias. CNS stimulants are contraindicated in animals with cardiovascular disease or glaucoma. CNS stimulants should not be given to patients with significant anxiety, because these symptoms may be exacerbated. Do not give CNS stimulants with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs. In case of overdose, the main goals are decontamination, control of body temperature, correction of any acid‐base and electrolytic disturbances, and symptomatic control of any CNS or cardiovascular symptoms. Removal of the stomach contents can be initiated with 3% hydrogen peroxide or apomorphine. However, if the patient is showing CNS signs, such as hyperactivity, do not induce emesis. In some cases, it can be beneficial to anesthetize the patient and conduct gastric lavage or nasogastric intubation and aspiration after an endotracheal tube has been placed and cuffed. Acepromazine or chlorpromazine may be beneficial in reducing the symptoms of hyperactivity, tremors, and other behavioral changes related to stimulation (Genovese et al. 2010). Diazepam is not recommended in dogs since it has caused cases of increased arousal in dogs with amphetamine toxicosis (Albretsen 2002). Propofol and phenobarbital can be used to control seizures, while propranolol can be used to control tachycardia. Muscle tremors can be controlled with methocarbamol (Genovese et al. 2010). Minimize external stimuli that will exacerbate the existing drug‐induced hyperexcitement. Provide supportive therapy, including procedures to cool the body if hyperthermia is occurring. True hyperkinesis, or ADD, appears to be rare in animals, but it has been identified in dogs. In a group of telomian dogs that had hyperkinetic syndrome and were therefore used as research models for the study of ADD in humans, dogs that responded to treatment with amphetamines were identified as being biochemically different from dogs that did not respond. Specifically, they had low levels of norepinephrine, dopamine, and homovanillic acid (HVA) in the brain and low levels of HVA in the cerebrospinal fluid (Bareggi et al. 1979a). However, if the chief complaint is hyperactivity, care should be taken to ensure that other, more common, possibilities are ruled out before a trial with a CNS stimulant is conducted. Young, healthy animals are normally very active. One possible cause of a complaint of hyperactivity is that the owner is simply not exercising their pet enough. Owners may have unrealistic expectations of how quiet and calm their pet will be or be keeping the pet in an unsuitable environment. For example, an elderly, sedentary couple living in a small apartment may get a Great Dane, supposedly for protection, and then find that they have a “hyperactive,” out‐of‐control pet on their hands because they are unable to meet the dog’s need for basic exercise. Sometimes owners unintentionally reinforce intensely active behaviors, especially in dogs and parrots. These and other pets may learn that they do not get attention when they are quiet, but they do get attention when they are noisy and rambunctious, specifically engaging in such behaviors as barking, screaming, spinning, running, or jumping. If the pet is primarily motivated by the need for social contact, even reprimands and screaming at the pet may simply make the problem worse. Owners of pet dogs may focus more on issues of training and consider the dog to be inattentive because it is not learning well in obedience school. In this case, again, environmental factors rather than a true pathology in the pet are likely to be the cause of the problem. Inappropriate training techniques include issues of failure to use appropriate reinforcers, use of inappropriate or excessive punishment, and inappropriate timing on the part of the trainer and/or owner can all result in failure of obedience training. In particular, the use of inappropriate and excessive punishment is quite common in dog training in the United States. This can lead to problems of chronic anxiety that interfere with the dog’s ability to learn because of emotional arousal. If a dog persists in hyperactive and/or inattentive behavior despite adequate exercise, reinforcement of quiet, calm behavior, ignoring of rambunctious behaviors, and appropriate obedience training techniques, it may have true hyperkinesis and respond to medication with CNS stimulants. Specifically look for: (i) a short attention span, (ii) constant movement, and (iii) failure to learn obedience, even with strong rewards. The truly hyperkinetic dog is likely to be unable to learn to sit on command, not because it does not want a delicious treat held over its head, but because it is unable to maintain the sitting position even for the brief moment required to reinforce a sit. Behavioral signs must have been present for an extended period of time and the patient must have been unresponsive to appropriate attempts to facilitate calmer behavior. Not all humans with ADD respond to medication, and this is likely to be the case with dogs. If a dog with an appropriate history becomes calmer and more attentive when given a CNS stimulant, the diagnosis of hyperkinesis is confirmed. It is important when working with families that have a hyperkinetic dog to discuss the fact that identifying a useful medication is just the beginning. Historically, the dog is likely to have not learned any basic obedience due to its inability to be attentive. Additionally, its previous hyperactivity may have led to the development of various bad habits that the owners have given up on. Once responsiveness to medication has been identified, it is important that appropriate training techniques, using positive reinforcement, be initiated immediately to teach the dog what is acceptable and desirable behavior. Table 15.1 gives the doses of CNS stimulants used for ADD in dogs. Table 15.1 Doses of CNS stimulants for dogs with true hyperkinesis or canine ADD. Note: Medication should only be given as needed, but can be repeated several times a day Amphetamines are believed to block reuptake of norepinephrine and dopamine into the presynaptic neuron and to increase the release of norepinephrine and dopamine into the extraneuronal space. They are noncatecholamine, sympathomimetic amines that stimulate the CNS. Peripherally, they stimulate both systolic and diastolic blood pressure, stimulate respiration, and dilate the bronchi (Shire US, Inc. 2003). Gastrointestinal acidifying agents will lower the absorption of any amphetamine, while urinary acidifying agents increase excretion. Thus, either type of medication will decrease the efficacy of amphetamine. In contrast, gastrointestinal alkalinizing agents increase the absorption of amphetamine, while urinary alkalinizing agents decrease the excretion of amphetamines. Either of these types of medications will therefore increase blood levels of amphetamines (GlaxoSmithKline 2003). In the dog, plasma levels of amphetamine peak at about 1.5 hours after oral administration, while cerebral spinal fluid (CSF) levels peak at about 2.5 hours (Bareggi et al. 1978). However, differences between breeds have been identified. Telomian‐beagle hybrids form less of the active metabolite of amphetamine, p‐hydroxyamphetamine, than do purebred beagles and exhibit less stereotypic behavior and hyperthermia when given the same dose of amphetamine (Bareggi et al. 1979b). Amphetamines are used to treat ADD and narcolepsy. Do not use amphetamines in patients that have known hypersensitivity to sympathomimetic amines, cardiovascular disease, hyperthyroidism, or glaucoma. Do not give amphetamines with an MAOI or within 14 days of discontinuing medication with an MAOI. Amphetamines can increase the activity of tricyclic antidepressants and any sympathomimetic agents. Avoid using these medications together. MAOIs and a metabolite of furazolidone decrease the rate of metabolism of amphetamines, thus increasing their effects and side effects. The CNS stimulant effects of amphetamines are blocked by a variety of drugs, including chlorpromazine, haloperidol, and lithium (GlaxoSmithKline 2003). Patients that do not have hyperkinesis will exhibit increased arousal and activity. Stereotypic behavior may also occur, as well as cardiac effects, including tachycardia, gastrointestinal disturbances, dry mouth, urticaria, and decreased libido. In dogs, D‐amphetamine is 1.4 times more potent than levo‐amphetamine in inducing stereotypic behavior. Doses of 1–2 mg kg−1 given as a single intravenous injection induce various stereotyped behavior, including bobbing, head turning, circling, pacing, and sniffing (Wallach et al. 1971). Amphetamines have been shown to have embryotoxic and teratogenic effects in mice, but not in rabbits. Human infants born to women addicted to amphetamines have increased risk of low birth weight and premature birth. They may also exhibit signs of withdrawal, including both agitation and lassitude. Amphetamines are excreted in milk (GlaxoSmithKline 2003). In case of overdose, conduct gastric lavage and give activated charcoal, cathartics, and sedatives. Acidifying the urine increases renal excretion, but increases the probability of acute renal myoglobinuria occurring. Chlorpromazine blocks the stimulant effects of amphetamines and can be used in the treatment of overdose. In rats, the LD50 (the dose that kills half of the animals tested) is 96.8 mg kg−1 (GlaxoSmithKline 2003). Chronic use can result in both tolerance and dependence. If a patient has been on amphetamines for an extended period, gradual withdrawal is recommended. Do not give amphetamines in the evening, because they may cause nighttime restlessness. Amphetamines may cause increases in plasma corticosteroid levels and interfere with measurements of urinary steroids (GlaxoSmithKline 2003). Healthy, fasted laboratory beagles given 2.5 mg kg−1 or 0.6 mg kg−1 amphetamine orally exhibited increased amounts of stereotypic behavior that peaked 2.5 hours after administration, as did CSF levels of amphetamine. Stereotypic behaviors were elevated between 2.5 and 6.5 hours after administration and then began to decrease. The relationship between stereotypic behavior and levels of amphetamine was exponential, suggesting that the amphetamine metabolite p‐hydroxyamphetamine contributes to stereotypic behavior when this drug is given. Increasing body temperature, on the other hand, has a linear relationship with the amount of amphetamine in the plasma, peaking at about 1.5 hours after administration, suggesting that this phenomenon is related to the presence of amphetamine in the plasma (Bareggi et al. 1978). In a telomian‐beagle hybrid used as a model for research on ADD in children, dogs exhibited hyperactivity, impulsiveness, and impaired learning ability. When these dogs are given D‐amphetamine, 1.2–2.0 mg kg−1 by mouth (PO), some dogs show significant improvement. Dogs that improved had higher peak blood levels of amphetamine than those that did not improve, and improvements paralleled blood levels of amphetamine (Bareggi et al. 1979b). Five of six pet dogs of various breeds diagnosed with canine hyperkinesis responded positively to treatment with D‐amphetamine at doses ranging from 0.21 mg kg−1 twice a day (b.i.d.) to 0.83 mg kg−1 b.i.d., although the duration of response varied. For some patients, the improvement was only transient, while for others the positive response was both substantial and permanent (Luescher 1993). Brown et al. (1987), during evaluation of a bull terrier with severe compulsive tail‐chasing, gave it a test dose of 1.0 mg kg−1 of D‐amphetamine orally. By subjective assessment, clinical signs worsened between two and four hours after administration of the D‐amphetamine. D‐amphetamine has been successfully used to treat narcolepsy in a long‐haired dachshund. However, treatment was discontinued because the dog also exhibited undesirable side effects, including hyperactivity, anorexia, excessive sniffing of the ground, and substantially increased activity of climbing into inaccessible spaces (Van Heerden and Eckersley 1989). Cats given 13 mg kg−1
CNS Stimulants
Action
Overview of Indications
Contraindications, Side Effects, and Adverse Events
Adverse Drug Interactions
Overdose
Clinical Guidelines
CNS stimulant
Dose
Dextroamphetamine
0.1–1.3 mg kg−1
Levoamphetamine
1–4 mg kg−1
Methylphenidate
2–4 mg kg−1
Specific Medications
I. Amphetamine
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Overdose
Discontinuation
Other Information
Effects Documented in Nonhuman Animals
Dogs
Cats
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