Dextroamphetamine and levamphetamine.

Amphetamines are molecules with an asymmetric carbon atom. As a result, amphetamines can exist as mirror images of each other. Such compounds are termed optical isomers or enantiomers. Dextroamphetamine and levamphetamine, whose structures are shown in Figure 36–1, illustrate the mirror-image concept. As we can see, dextroamphetamine and levamphetamine both contain the same atomic components, but those components are arranged differently around the asymmetric carbon. Because of this structural difference, these compounds have somewhat different properties. For example, dextroamphetamine is more selective than levamphetamine for causing stimulation of the CNS, and hence produces fewer peripheral side effects.

Amphetamine.

The term amphetamine refers not to a single compound but rather to a 50:50 mixture of dextroamphetamine and levamphetamine. (In chemistry, we refer to such equimolar mixtures of enantiomers as racemic.)

Lisdexamfetamine.

Lisdexamfetamine [Vyvanse], introduced in 2007, is a prodrug composed of dextroamphetamine covalently linked to l-lysine. Following oral dosing, the drug undergoes rapid hydrolysis by enzymes in the intestine and liver to yield lysine and free dextroamphetamine, the active form of the drug. If lisdexamfetamine is inhaled or injected, hydrolysis will not take place, and hence the drug is not effective by these routes. Accordingly, it may have a lower abuse potential than other forms of amphetamine.

Methamphetamine.

Methamphetamine is simply dextroamphetamine with an additional methyl group (see Fig. 36–1).

Central nervous system.

The amphetamines have prominent effects on mood and arousal. At usual doses, they increase wakefulness and alertness, reduce fatigue, elevate mood, and augment self-confidence and initiative. Euphoria, talkativeness, and increased motor activity are likely. Task performance that had been reduced by fatigue or boredom improves.

Amphetamines can stimulate respiration, and suppress appetite and perception of pain. Stimulation of the medullary respiratory center increases respiration. Effects on the hypothalamic feeding center depress appetite. By a mechanism that is not understood, amphetamines can enhance the analgesic effects of morphine and other opioids.

Cardiovascular system.

Cardiovascular effects occur secondary to release of NE from sympathetic neurons. Norepinephrine acts in the heart to increase heart rate, atrioventricular (AV) conduction, and force of contraction. Excessive cardiac stimulation can cause dysrhythmias. In blood vessels, NE promotes constriction. Excessive vasoconstriction can cause hypertension.

CNS stimulation.

Stimulation of the CNS can cause insomnia, restlessness, and extreme loquaciousness. These effects can occur at therapeutic doses.

Weight loss.

By suppressing appetite, amphetamines can cause weight loss. For people who are lean to start with, weight loss is considered an adverse effect. Conversely, for people who are obese, weight loss is desirable.

Cardiovascular effects.

At recommended doses, stimulants produce a small increase in heart rate and blood pressure. For most patients, these increases lack clinical significance. However, for patients with pre-existing cardiovascular disease, dysrhythmias, anginal pain, or hypertension might result. Accordingly, amphetamines must be employed with extreme caution in these people. Any patient who develops cardiovascular symptoms (eg, chest pain, shortness of breath, fainting) while using a stimulant should be evaluated immediately.

Do amphetamines increase the risk of sudden death? Probably not. And should children routinely receive an electrocardiogram (ECG) before using these drugs? Probably not—despite a 2008 statement from the American Heart Association (AHA) saying it would be reasonable to consider obtaining an ECG in children being evaluated for stimulant therapy of ADHD. Why is the AHA concerned? Because 14 children, 5 with heart defects, died suddenly while using Adderall, a mixture of amphetamine and dextroamphetamine. However, given that millions of children have used the drug, the death rate is no greater than would be expected for a group this size, whether or not Adderall was being used. The bottom line? First, there are no data showing that stimulants increase the risk of sudden death, even in children with heart disease. Second, there are no data showing that limiting the use of stimulants in children with heart defects will protect them from sudden death. And third, there are no data showing that screening for heart disease with an ECG before starting stimulants will be of benefit. Therefore, it would seem that routine ECGs are unnecessary before starting a child on stimulant therapy, especially if there is no evidence of heart disease. However, if there is evidence of heart disease, an ECG might be appropriate.

Psychosis.

Excessive amphetamine use produces a state of paranoid psychosis, characterized by hallucinations and paranoid delusions (suspiciousness, feelings of being watched). Amphetamine-induced psychosis looks very much like schizophrenia. Symptoms are thought to result from release of DA. Consistent with this hypothesis is the observation that symptoms can be alleviated with a DA receptor blocking agent (eg, haloperidol). Following amphetamine withdrawal, psychosis usually resolves spontaneously within a week.

In some individuals, amphetamines can unmask latent schizophrenia. For these people, symptoms of psychosis do not clear spontaneously, and hence psychiatric care is indicated.

Attention-deficit/hyperactivity disorder.

The role of amphetamines in ADHD is discussed later.

Narcolepsy.

Narcolepsy is a disorder characterized by daytime somnolence and uncontrollable attacks of sleep. By stimulating the CNS, amphetamines can promote arousal and thereby alleviate symptoms.

Obesity.

Because they suppress appetite, amphetamines have been employed in programs for weight loss. However, because of their high potential for abuse, and because they offer no advantages over less dangerous drugs, amphetamines are not recommended for weight reduction.