Sources

The amphetamine class of drugs consists of a number of derivative mole-cules that are structurally related to the parent compound amphetamine. Amphetamine is the common name for alpha-methylphenylethylamine, and is a member of the family of phenylethylamines. Numerous substitutions are possible, resulting in a number of amphetamine analogues. They are subject to close regulation under the federal CSA of 1970. Amphetamine itself is no longer used in veterinary medicine. Before the CSA was passed, amphetamine was used as a central nervous system (CNS) and respiratory stimulant in dogs to overcome the depressant effects of barbiturates.²

There are a large number of legitimate amphetamine pharmaceuticals that contain various amphetamine analogues. They are indicated for the treatment of obesity, attention deficit disorder (ADD), and narcolepsy in humans. By far, most small animal exposures occur as accidental ingestions of these prescribed medications. Table 17-1 lists the most commonly prescribed amphetamines, their trade names, and therapeutic uses. Illegal amphetamine production also occurs in clandestine laboratories. Some street names include “speed,” “uppers,” “dex,” “dexies,” and “bennies” for amphetamine,³ “ice” and “glass” for the clear, translucent crystals of methamphetamine, and “crystal,” “crank,” and “meth” for the white or yellow powder form of methamphetamine.³ Designer amphet-amines include 4-methylaminorex (“ice,” “U4EUh”), 3,4-methylene-dioxymethamphetamine (MDMA [“ecstasy,” “XTC,” “Adam,” “MDA”]), 3,4-methylenedioxy-N-ethylamphetamine (MDEA [“Eve”]), and methcathinone (“cat”).⁴ Ritalin (methylphenidate) has become an increasingly popular stimulant in college students studying for exams. The U.S. DEA reports Ritalin as one of the most frequently stolen medications.⁵

Table 17-1 Some Prescription Amphetamine Products, Their Trade Names, and Therapeutic Uses

* Marketing was discontinued in 1997 because of the associated incidence of cardiac valvulopathy.¹⁵

Toxic dose

The oral median lethal dose (LD₅₀) for amphetamine sulfate in the dog is 20 to 27 mg/kg, and for methamphetamine hydrochloride it is 9 to 11 mg/kg.⁶ The intravenous (IV) LD₅₀ for amphetamine in the dog is 5.85 mg/kg.⁷ Death from methamphetamine has been reported in humans at a dose of 1.5 mg/kg.⁸

Toxicokinetics

In general amphetamines are well absorbed orally with peak plasma levels occurring by 1 to 3 hours. Sustained-release preparations have a slower rate of absorption, and peak levels are delayed. Amphetamines are highly lipophilic, readily crossing the blood-brain barrier.³ They undergo hepatic metabolism, and both unchanged amphetamine and its metabolites are excreted in the urine. Some metabolites may be pharmacologically active.³ Renal excretion of unchanged amphetamine is pH dependent, with an acidic urine greatly enhancing elimination.^3,9 The half-life in humans with a urine pH of less than 6.6 is 7 to 14 hours, whereas it is 18 to 34 hours in those with a urine pH of greater than 6.7.¹⁰ A study in dogs demonstrated a half-life of 6.13 hours at a urine pH of 7.5 and 3.67 hours at a urine pH of 5.96.¹¹

Mechanism of toxicity

The exact mechanism for the central nervous system effects of the amphetamines is unknown, but they have a stimulant effect on the cerebral cortex and on the reticular-activating system⁹ and on the medullary respiratory center.¹² Peripherally, amphetamines cause release of norepinephrine from adrenergic nerve terminals and have a direct stimulant effect on α-adrenergic and β-adrenergic receptors.⁹ They are also inhibitors of monoamine oxidase, thus depressing catecholamine metabolism.¹² Amphetamine is a dopamine excitatory receptor agonist and can be blocked centrally by phenothiazine derivatives that have dopamine excitatory receptor antagonism.¹³

Clinical signs

Signs expected following exposure to an amphetamine include hyperactivity, restlessness, mydriasis, hypersalivation, vocalization, tachypnea, tremors, hyperthermia, ataxia, seizures, and tachycardia. Some animals exhibit depression, weakness, and bradycardia.

Minimum database

The minimum database should include a serum chemistry profile and blood gas analysis in symptomatic animals to determine acid-base status, electrolyte abnormalities, and the extent of hypoglycemia. The cardiac rate and rhythm should be monitored for tachyarrhythmias. Animals should also be observed for signs of CNS stimulation and hyperthermia.

Confirmatory tests

Amphetamines can be detected in blood, urine, and saliva. Consultation with a diagnostic toxicologist is recommended before sample submission.

Treatment and prognosis

For recent exposures (less than 30 minutes) emesis can be induced and activated charcoal administered. The animal should then be monitored closely for signs of amphetamine toxicosis. For extremely large ingestions or for animals exhibiting clinical signs, gastric lavage followed by activated charcoal is indicated. Sustained-release preparations may require repeated doses of activated charcoal.

Seizures have been successfully controlled with diazepam, pentobarbital, or propofol. However, benzodiazepines may paradoxically exacerbate the neurological effects from amphetamines and are generally not recommended. Chlorpromazine given (IV) at 10 to 18 mg/kg prevented lethal effects of amphetamine in experimentally dosed dogs¹⁴ and has also been recommended for controlling CNS excitation and seizures because of its dopamine excitatory receptor antagonist properties.¹³ Phenothiazines should be used with the knowledge that they may lower the seizure threshold. Hyperthermia should be corrected using cool IV fluids, ice packs, fans, or cool water baths. Animals should be closely monitored to prevent subsequent hypothermia.

Tachyarrhythmias can be controlled with a beta blocker, such as propranolol or metoprolol. Ventricular dysrhythmias can be treated with lidocaine.

IV fluids are necessary to maintain renal function and promote elimination of amphetamines. Urinary acidification using ascorbic acid or ammonium chloride has been shown to enhance the elimination of amphetamine,¹⁰ but this procedure is contraindicated if the patient’s acid-base status cannot be closely monitored or if myoglobinuria is present. Intense muscle activity caused by tremors or seizures can result in a metabolic acidosis and rhabdomyolysis. Fluid diuresis will help to prevent acute renal failure from myoglobinuria secondary to rhabdomyolysis, which is very rare but can occur.

Prognosis depends on the severity and duration of clinical signs at presentation. Trauma, hypoxia, hyperthermia, or cerebral edema can result from uncontrolled seizure activity. Renal failure can result from myoglobinuria (rare) and acidosis.

Differential diagnoses

Other agents that can cause CNS stimulation should be included in the differential diagnosis list. These include methylxanthines, metaldehyde, tremorgenic mycotoxins, pseudoephedrine, strychnine, tricyclic antidepressants, permethrin (cats), 5-fluorouracil, organochlorine insecticides, organophosphorus and carbamate insecticides, 4-aminopyridine, sodium ion toxicosis, lead, and herbal preparations containing ma huang, guarana root, or ephedra.

Sources

The barbiturates as a class are barbituric acid derivatives. Barbituric acid itself has no CNS activity. Various side chain substitutions on barbituric acid influence the particular barbiturate’s lipophilicity, potency, and rate of elimination. The barbiturates are used therapeutically as sedatives and anticonvulsants and to induce anesthesia. Barbiturate use has declined in favor of safer alternatives, such as the benzodiazepines.¹⁶ The barbiturates have been classified as ultrashort-, short-, intermediate-, or long-acting based on their duration of action (0.3, 3, 3 to 6, and 6 to 12 hours, respectively).¹⁷ Table 17-2 lists the most common barbiturate preparations, trade names, and classifications based on duration of action. Primidone is a phenobarbital congener that is metabolized to produce phenobarbital and phenylethylmalonamide. The parent compound and its metabolites have anticonvulsant activity.

Table 17-2 Some Pharmaceutical Barbiturates Classified According to Duration of Action

Most small animal exposures occur as a result of accidental ingestion of human or veterinary prescription preparations. However, toxicoses have also resulted from iatrogenic overdose, ingestion of illicit preparations (known as “downers,” “reds,” “Christmas trees,” and “dolls”),¹⁸ accidental administration of euthanasia solutions, and ingestion of tissue of euthanized animals.^19,20 The barbiturate found in most euthanasia solutions is pentobarbital. Table 17-3 lists some commonly used euthanasia solutions and their active ingredients. Recently the Food and Drug Administration’s Center for Veterinary Medicine added an environmental warning to labels of pentobarbital-containing euthanasia solutions.²¹ Veterinarians and animal owners are responsible for proper disposal of euthanized carcasses. Accidental poisoning of wildlife who scavenge euthanized carcasses may result in criminal penalties for the animal owner and veterinarian.^22,23

Table 17-3 Trade Names of Some Euthanasia Solutions and Their Active Ingredients

* T-61 was a widely used euthanasia solution and was not subject to the CSA of 1970. It contains no barbiturate but a narcotic analgesic (embutramide), a neuromuscular blocker to cause skeletal muscle relaxation (mebezonium), and a local anesthetic (tetracaine).

Toxic dose

The oral LD₅₀ for phenobarbital in the dog is 150 mg/kg; the minimum published oral lethal dose (LD_L0) for phenobarbital in the cat is 125 mg/kg.¹⁸

Toxicokinetics

The barbiturates are well absorbed orally or following intramuscular (IM) injection. The sodium salts are more rapidly absorbed than the free acids. Lipid solubility of the drug determines distribution of the barbiturate in the body and thus the duration of action. Short-acting barbiturate anesthetics (e.g., thiamylal) are highly lipid soluble, are distributed into all body tissues (including the brain) very rapidly, and then are redistributed very rapidly into fat and total body water. The anesthetic effect is terminated when the drug exits the brain. Less lipophilic barbiturates enter and leave the brain more slowly, resulting in a more gradual onset and longer duration of action (e.g., phenobarbital). Because of the rapid distribution phase of the highly lipophilic anesthetic barbiturates, it is difficult to correlate true half-life with duration of action for these compounds.¹⁷

The barbiturates are metabolized in the liver by hepatic microsomal enzymes and both unchanged compound and metabolites are excreted in the urine. Acutely the barbiturates may bind to P450 enzymes and interfere with the metabolism of other compounds. Chronic use of barbiturates increases hepatic microsomal enzyme activity (e.g., enzyme induction) and can accelerate biotransformation of exogenous and some endogenous substances (e.g., steroids). In very young or very old animals or those with hepatic disease, metabolism of barbiturates may be slow, resulting in a prolonged half-life. About 25% of phenobarbital is excreted unchanged in the urine. Urine alkalinization enhances phenobarbital excretion by ion trapping.¹⁷ For phenobarbital, urinary alkalinization can increase excretion fivefold to tenfold. Urine alkalinization is ineffective for the short-acting barbiturates because they are more highly protein bound, have higher pK_a values, and are primarily metabolized by the liver with very little urinary excretion.²⁴

Mechanism of toxicity

The barbiturates activate inhibitory γ-aminobutyric acid-a (GABA_a) receptors and inhibit excitatory glutamate receptors.¹⁶ They can also inhibit the release of norepinephrine and acetylcholine.²⁵ They are considered CNS depressants, but in some patients they can produce excitement. High doses of barbiturates suppress the hypoxic drive and the chemoreceptor drive, resulting in respiratory depression. Anesthetic concentrations of barbiturates can depress sodium and potassium channels in the heart, and direct depression of cardiac contractility occurs at extremely high doses.¹⁶ Severe oliguria or anuria may occur because of extreme hypotension in patients with acute barbiturate intoxication.

Clinical signs

Clinical signs include depression, ataxia, incoordination, weakness, disorientation, recumbency, coma, hypothermia, tachycardia or bradycardia, and death.

Minimum database

A complete serum blood count and chemistry profile should be performed, and acid-base status should be evaluated in patients exhibiting severe clinical signs. Cardiac and respiratory function should be evaluated.

Confirmatory tests

Barbiturates can be detected in stomach contents, blood, urine, and feces. Consultation with a veterinary diagnostic toxicologist is recommended before sample submission.

Treatment and prognosis

For recent ingestions, emesis followed by repeated doses of activated charcoal and a cathartic should be administered. For animals exhibiting severe depression, emesis is contraindicated because of the risk of aspiration. In these cases, gastric lavage should be performed, followed by repeated doses of activated charcoal and a cathartic. Magnesium-containing cathartics (Epsom salts) should be avoided because magnesium may exacerbate CNS depression.²⁶ It has been shown that repeated doses of activated charcoal greatly reduce the plasma half-life of phenobarbital.^27–31 Activated charcoal acts as a “sink” to enhance diffusion of barbiturates from the circulation into the gastrointestinal tract, even for compounds given parenterally.²⁵

Respiratory depression is the major cause of death, so initial treatment should include assessment of respiratory function. Intubation, administration of oxygen, and assisted ventilation may be required. Hypothermia is a common sequela in severely depressed animals and should be monitored and corrected. Cardiac monitoring is required because some barbiturates (e.g., thiopental sodium and thiamylal sodium) are arrhythmogenic.²⁶ Also, profound hypothermia resulting from barbiturate intoxication can cause ventricular fibrillation and cardiac arrest.¹⁷

Some barbiturates undergo hepatic metabolism with renal excretion, so increased renal blood flow with IV fluids may enhance elimination. Forced alkaline diuresis may promote removal of some barbiturates, especially phenobarbital, which is subject to ion trapping in the urine.¹⁷

Differential diagnoses

Other causes of CNS and respiratory depression should be included in the differential diagnosis. These include benzodiazepines, xylitol, macrolide antiparasiticides (e.g., ivermectin), encephalopathies, amitraz, ethanol, ethylene glycol, propylene glycol, diethylene glycol, methanol, isopropanol, acetone, phenothiazines, opioids, and hypoglycemia.

Sources

The benzodiazepines are used as sedatives, antianxiety agents, and anticonvulsants. The first benzodiazepine, chlordiazepoxide, was synthesized by accident in 1961 by the laboratories of Hoffman La Roche.³² The term benzodiazepine refers to the chemical structure of the compound: a benzene ring bound to a seven-member diazepine ring. Modifications in this structure have led to the development of a number of benzodiazepine derivatives that vary in therapeutic use and half-life. Table 17-4 lists some of the commonly used benzodiazepines and their trade names. All of the benzodiazepines are schedule C-IV drugs according to the CSA of 1970. Most small animal exposures result from ingestion of prescription formulations. Recently a very potent benzodiazepine, flunitrazepam (Rohypnol), has made its way into illicit use. It is a “date rape” drug and produces sedation in humans within 20 to 30 minutes that may last for hours.³³

Table 17-4 Some Common Benzodiazepines and Their Trade Names

Toxic dose

The oral LD₅₀ for diazepam in the rat is 249 mg/kg and for the mouse, 48 mg/kg. The IV LD₅₀ in the rat and mouse is 32 and 25 mg/kg, respectively.³⁴ The oral LD₅₀ of alprazolam in the rat and mouse is 1220 and 770 mg/kg, respectively.³⁴

Toxicokinetics

The benzodiazepines are well absorbed from the gastrointestinal tract. They are highly lipid soluble and highly protein bound. The benzodiazepines are widely and rapidly distributed in brain, liver, and spleen and are then more slowly redistributed to more poorly perfused sites, such as adipose tissue and muscle.³⁵ Biotransformation occurs in the liver, and some benzodiazepines produce active metabolites with half-lives that exceed those of the parent compound. Conjugation with glucuronide occurs with elimination in the urine.³⁶ Benzodiazepines without major active metabolites include alprazolam, clonazepam, oxazepam, temazepam, and triazolam.^33,37

The major metabolite of diazepam in the dog is nordiazepam. It is just as pharmacologically active on the CNS as diazepam.³⁸ The plasma half-life of diazepam following IV injection in the dog is 2.4 hours; the half-life of nordiazepam is 2.85 hours. In the cat, the mean elimination half-life of diazepam is 5.46 hours, and of nordiazepam it is 21.3 hours following IV administration.³⁸