Chapter: Modern Pharmacology with Clinical Applications: Central Nervous System Stimulants

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Psychomotor Stimulants

Many psychomotor stimulants possess activities similar to those of amphetamine and have been discussed pre-viously .

PSYCHOMOTOR STIMULANTS

Pharmacokinetics

Many psychomotor stimulants possess activities similar to those of amphetamine and have been discussed pre-viously . Of primary importance to our discussion of the psychomotor stimulants are ampheta-mine (Adderall, Benzedrine, Dexedrine), methampheta-mine (Desoxyn), and methylphenidate (Concerta, Ritalin, Metadate, Methylin).

All of these compounds are well absorbed after oral administration, leaving injectable forms with few legiti-mate applications. Although several catabolic pathways metabolize the amphetamines, a considerable portion of untransformed drug is excreted in the urine. Thus, it is possible to ion-trap this weak organic base by acidify-ing the urine, thereby reducing its reabsorption in the renal tubules and enhancing its clearance.

Mechanism of Action

There is good evidence that the facilitation of peripheral sympathetic nervous system transmission produced by the amphetamines also occurs in the CNS. The possibility that amphetamines act indirectly (i.e., by releasing monoamines) at monoaminergic synapses in the brain and spinal cord seems likely. However, amphetamine has effects beyond displacement of catecholamines; these in-clude inhibition of neuronal amine uptake, direct stimula-tion of dopamine and serotonin receptors, antagonism of catecholamine action at certain subtypes of adrenocep-tors, and inhibition of monoamine oxidase. Interestingly, none of these actions explains the therapeutic benefit of the amphetamines in hyperkinetic children.

Clinical Uses

The therapeutic indications for the psychomotor stimu-lants are quite limited. They are beneficial in the treat-ment of the hyperkinetic syndrome (attention deficit– hyperactivity disorder with minimal brain dysfunction). This is generally a childhood disease characterized by hyperactivity, inability to concentrate, and impulsive be-havior. Amphetamines and the more extensively used methylphenidate paradoxically are quite effective in calming a large proportion of children with this disor-der. Pemoline (Cylert) is also used in the treatment of attention deficit disorder with hyperkinetic behavior. The mechanism by which these compounds are effec-tive in this disorder is not known.

Narcolepsy is another medically recognized indica-tion for the use of the psychomotor stimulants. This dis-order is characterized by sleep attacks, particularly dur-ing the day, sudden loss of muscle tone (cataplexy), sleep paralysis, and vivid visual and auditory nightmares that may persist into the waking state. Drugs that influ-ence the central action of adrenomimetic amines re- markably affect narcolepsy. Monoamine oxidase in-hibitors (e.g., selegiline) and amphetamines are both quite effective in preventing sleep attacks and improv-ing cataplexy. Modafinil (Provigil) is a nonampheta-mine compound whose mechanism of action is not known but that has been shown to be successful in the treatment of narcolepsy. However, amphetamine and methylphenidate are still considered among the drugs of choice in this disorder.

Previously, another use of the amphetamines and other centrally acting adrenomimetics has been in the management of obesity and weight reduction. Although the amphetamines have a significant anorexic effect, tolerance to this action develops within a few weeks. In addition, insomnia restricted their use during the latter part of the day. The combined drawbacks of the devel-opment of tolerance and potential for drug abuse have convinced much of the medical community that the use of amphetamines in weight control is inappropriate.

Fenfluramine (Pondimin) and phentermine (Adipex-P, Fastin) are anorexigenic drugs that produce depres-sion of the CNS and at one time were used (Fen-phen) in the treatment of obesity. Sibutramine (Meridia) is also available for the treatment of obesity.

Adverse Effects

The acute effects of psychomotor stimulant overdoses are related to their CNS stimulant properties and may include euphoria, dizziness, tremor, irritability, and in-somnia. At higher doses, convulsions and coma may en-sue. These drugs are cardiac stimulants and may cause headache, palpitation, cardiac arrhythmias, anginal pain, and either hypotension or hypertension. Dextro-amphetamine produces somewhat less cardiac stimula-tion. Chronic intoxication, in addition to these symp-toms, commonly results in weight loss and a psychotic reaction that is often diagnosed as schizophrenia.

These agents produce addiction, including psycholog-ical dependence, tolerance, and physical dependence. Psychic dependence also has been seen following high doses of methylphenidate.The abstinence syndrome seen after abrupt discontinuation of amphetamines is neither as dramatic nor as predictable as that observed during withdrawal from the barbiturates or opioids. With the amphetamines, the abstinence syndrome consists prima-rily of prolonged sleep, fatigue, and extreme hunger (hy-perphagia). These symptoms may be accompanied by profound and long-lasting depression. 

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