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CNS stimulants and anorectics

CNS stimulants induce wakefulness, alertness, decreased sense of fatigue, euphoria without improving depressive mood.

Amphetamine

Amphetamine increases release and inhibits reuptake of dopamine and noradrenaline, perhaps also of serotonin.

Amphetamine, which is a racemic, and dextroamphetamine, the d-form enantiomer, have peripheral effects, particularly cardiovascular effects, but their central effects prevail. In moderate and high doses, amphetamine stimulates vigilance, decreases sleep requirement and fatigue, reduces appetite (appetite suppressant effect). It was used in therapeutics as vigilance stimulant and anorectic. In many countries, it was withdrawn from the market because of its cardiovascular and neuropsychiatric adverse effects and especially because of the risk of addiction.

Amphetamine and dextroamphetamine

ADDERALL* Tablets, Capsules

Dextroamphetamine

DEXEDRINE*
DEXTROSTAT* Tablets

Amphetamine and derivatives such as methamphetamine (“ice”), methylene dioxy-amphetamine (MDA), methylene dioxymethamphetamine (MDMA or “ecstasy”), cathinone (present in Khat), are used by abusers by oral intake or fast intravenous injections. These compounds, used in large or repeated doses by addicts, can induce true psychotic states (delusion of persecution, stereotyped behavior, autism) with absence of sleep and loss of weight.

Certain people having consumed amphetamine derivatives and hallucinogenic agents can experience, in the absence of new intake, symptoms looking like those they had at the time of the intake. This phenomenon is called “flashback”.

Amphetaminic anorexiants

Amphetamine is not used any more in therapeutics but some of its derivatives, classified among anorexiants, were until a recent date: amfepramone, clobenzorex, mefenorex and fenproporex. These products reduce appetite and were used in the treatment of obesity.

The principal adverse effects of these anorexiants are excitation with nervousness and insomnia, palpitations, tachycardia. Addiction is possible and a depressive tendency could be observed at their discontinuation.

Epidemiologic studies showed that amphetaminic anorexiants - as well as fenfluramine which has serotoninomimetic properties - could, especially in prolonged use, elicit pulmonary arterial hypertension, rare but severe adverse effect, as well as alteration of cardiac valves. Because of these risks, the duration of their prescription was reduced to less than three months before they were withdrawn from the market. The anorexiant now frequently used is sibutramine.

Sibutramine is an inhibitor of the reuptake of monoamines, noradrenaline, serotonin and dopamine. It was not active as an antidepressant but is active as an appetite suppressant facilitating the loss of weight. In addition to its appetite suppressant effect, sibutramine increases thermogenesis and fatty acid catabolism, perhaps by stimulation of the beta-3 adrenergic receptors. Sibutramine is itself active but its activity results mainly from that of 2 of its metabolites resulting from 2 successive demethylations catalysed by a cytochrome P450, CYP3A4.

 


The most frequent adverse effects of sibutramine are insomnia, constipation, mouth dryness, headache, tachycardia, palpitations, hypertension. For women of age to procreate, contraception is necessary before prescription of a treatment by sibutramine

Sibutramine

MERIDIA* Capsules

Other stimulants

Methylphenidate inhibits dopamine and noradrenaline reuptake and is used clinically in a paradoxical therapeutic indication, the management of hyperactivity disorders with lack of attention in children.

Its principal adverse effects are: irritability, insomnia, decrease of appetite, appearance of stereotyped movements and, exceptionally, delusion and hallucinations.

Methylphenidate

RITALIN* Tablets
METADATE* Capsules, Tablets
CONCERTA* Extended-Release tablets

Fenozolone is another amphetaminic derivative with psychostimulant effects.

Cocaine

Cocaine inhibits the reuptake of catecholamines, dopamine and noradrenaline. It has moreover a local anesthetic effect but is not used in therapeutics. Cocaine is a substance of abuse. It is taken by oral, nasal, pulmonary and intravenous routes. Cocaine base, called crack when smoked, is as active and toxic as intravenous preparations. Intensity of psychic effects depends on the rate at which its cerebral concentration increases. In fast administration, it induces an intense state of euphoria of short duration followed by a dysphoric state which pushes to repeat intakes several times per day. Its action resembles that of amphetamine but is of much shorter duration, half an hour instead of approximately ten hours.

Chronic use of cocaine, like that of amphetamine, can cause psychotic reactions - delusion ,stereotyped and autistic behaviour with loss of the sense of responsibility - and in addition, an increase in cardiovascular accidents with premature atherosclerosis.

Immediate toxic effects of cocaine are tachycardia, ventricular arrhythmia, chest pain, myocardial infarction, arterial hypertension, hyperthermia and seizures.

Addiction to cocaine is very strong in human beings and in animal experiments.

Cocaine is metabolized primarily to benzoylecgonine which can be detected in urines during two or three days after a single intake.

In case of concomitant intake of cocaine and alcohol in important quantity, benzoylecgonine is converted in the body to ethyl ester derivative, called cocaethylene, which has properties similar to those of cocaine.

Remarks

  1. CART (cocaine and amphetamine regulated transcrit) corresponds to RNA messenger induced by administration of cocaine or amphetamine. This RNA messenger leads to synthesis of a prepro-protein which by hydrolysis gives polypeptides of smaller molecular weight which reduce food intake. The receptors of these polypeptides have not been described.
  2. Tyramine increases noradrenaline release. It is not used in therapeutics but, because it is present in certain cheeses, if eaten can cause hypertensive accidents in patients, treated by MAOI, particularly nonspecific and irreversible inhibitors.. The MAOI raise tissue catecholamines and inhibit tyramine inactivation by MAO. Thus, tyramine releases large amounts of catecholamines, responsible for hypertensive accesses which must be treated by alpha-1adrenolytics. This explains why MAOI should not be used at the same time as indirectly acting sympathomimetic drugs.
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