Excerpt from Toxicity, Amphetamine

Synonyms, Key Words, and Related Terms: amphetamine toxicity, amphetamines, amphetamine overdose, amphetamine intoxification, amphetamine intoxication, drug overdose, synthetic amphetamine compounds, diet pills, prescription medication abuse, methamphetamines, meth, biogenic amine, stimulant overdose, stimulant abuse, methylenedioxymethamphetamine, MDMA, Ecstasy, tachycardia, cardiac dysrhythmia, hypertension, hyperthermia, seizure, psychosis, stroke

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Background: Amphetamines are a class of compounds increasingly abused in regions of the world such as the western United States and Europe. Synthetic amphetamine compounds commonly are produced in clandestine laboratories and vary in purity and potency. Other potentials for amphetamine abuse include prescription medications and various over-the-counter diet pills.

Clinical effects of amphetamine abuse are significant and commonly observed in EDs. The ED physician’s ability to recognize and treat amphetamine intoxication is very important.

The phenylethylamine structure of amphetamines (see Image 1) is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions. The relative activities that amphetamines have to stimulate the receptors of these biogenic amines are dependent on the chemical substituents on the amphetamine molecule; thus, the clinical presentation is dependent on the type of amphetamine used. For example, methamphetamine lacks much of the peripheral stimulant properties of amphetamine while still offering euphoric and hallucinogenic properties. These actions are similar to those of cocaine; however, while effects of cocaine last for 10-20 minutes, duration of amphetamine action is much longer, lasting as long as 10-12 hours.

The routes of amphetamine administration may be oral (ingestion), inhalation (smoke), or injection (IV). Oral use is associated with an approximate one-hour lag time before onset of symptoms, whereas inhaled and IV methods yield effects within a few minutes. Peak plasma concentrations occur in 5 minutes with IV use, 30 minutes with nasal or IM use, and 2-3 hours postingestion.

Pathophysiology: Amphetamines are a group of structurally related compounds that produce central nervous system (CNS) and peripheral nervous system (PNS) stimulation.

Central nervous system

Amphetamine compounds cause a general efflux of biogenic amines from neuronal synaptic terminals (indirect sympathomimetics). They inhibit specific transporters responsible for reuptake of biogenic amines from the synaptic nerve ending and presynaptic vesicles. Amphetamines also inhibit monoamine oxidase, which degrades biogenic amine neurotransmitters intracellularly. The net effect is an increase of neurotransmitter release into the synapse. Physiological adaptation occurs through receptor or coupling down-regulation; this tolerance and an accompanying psychological tolerance can lead to escalating use of the drug and increased toxicity. Chronic use can lead to a depletion of biogenic amine stores and a paradoxical reverse effect of the drug—a wash out.

Elevated catecholamine levels usually lead to a state of increased arousal and decreased fatigue. Increased dopamine levels at synapses in the CNS may be responsible for movement disorders, schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic aspects of these drugs.

Other serotonergic and dopaminergic effects may include resetting the thermal regulatory circuits upward in the hypothalamus and causing hyperthermia. The hyperthermia produced by amphetamines is similar to that of the serotonin syndrome.

Laboratory studies reveal that amphetamines interfere with the normal control of the neurohumoral (hypothalamopituitary) axis, affecting secretion of such factors as ACTH. Amphetamines may alter other neural functions such as complex behavioral and learning patternings; this may be important for understanding effects of amphetamine use during pregnancy.

Animal studies indicate that amphetamines interact with N-methyl-D-aspartate (NMDA) receptors on serotonergic neurons, leading to neuronal destruction. This interaction may contribute to seizure activity.

In vitro, amphetamines have been found to stimulate regulatory molecules, such as the .....