Amphetamines interaction with other drugs

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

Unexpected neurotoxicity from amphetamine and its analogs (e.g. 3,4 methylenedioxymethamphetamine, also known as ecstasy ) as well as interactions with other drugs subject to CYP2D6 polymorphism would likewise be expected to occur more frequently among Africans and Caucasians than in Asians.(112)... 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Many other adrenomimetic drugs, such as amphetamine, do not themselves interact with adrenoceptors, yet they produce sympathetic effects by releasing norepinephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells. These adrenomimetics are called indirectly acting adrenomimetic drugs. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine. 

Drugs that alter sleep produce their effects on the brain by altering the actions of neurotransmitters and consequently how neurons communicate with each other. However, different drugs can alter the actions of neurotransmitters in different ways. Stimulants such as amphetamine cause neurons to release excess amounts of neurotransmitters like dopamine and serotonin. Other drugs, such as the prescription sleeping pills Halcion or Ambien or antihistamines, can interact directly with the neurons receptors to either enhance or block the effects of the neurotransmitters. In later chapters, we will discuss how drugs that help you sleep or stay awake alter the chemistry of the brain. 

Robbins TW, Watson DA, Gaskin M, Ennis C (1983) Contrasting interactions of pipradrol, d-amphetamine, cocaine, cocaine analogues, apomorphine and other drugs with conditioned reinforc-mento. Psychopharmacol 50 113-119. 

Dexamphetamine is one of the most powerful and best known psychomotor stimulants, and other similar agents include dexfenfluramine. diethylpropion and fenfluramine. All these are on the controlled drugs list, and have a limited medical use as appetite suppressants. Such drugs work by interacting with the release of monoamines within the central (and peripheral) nervous system, and can be regarded as indirect SYMPATHOMIMEtics. Recently, there has been some use of the weak amphetamine-like stimulant methylphenidate to treat attention-deficient hyperactivity disorder (ADHD) in children. 

Interactions of MAOIs with other sympathomimetic drugs are well known. The increased neuronal stores of NE represent a booby-trap hazard that can easily be triggered by indirectly acting adrenergic agents such as the amphetamines found in many antiobesity preparations. Drugs such as ephedrine, phenylpropanolamine, and phenylephrine are potentially more dangerous because of their ready availability to the public in over-the-counter medications such as cold medicines and nose drops. 

The phenylalkylamines mescaline, 2,5-dimethoxy-4-methyl amphetamine (DOM) and 3,4-dimethoxyphenylethylamine had no effects on caeruloplasmin — they were neither substrates nor did they modify the oxidation of known substrates. In other studies on the substrate specificity of caeruloplasmin it was noted that, in addition to being a substrate, 3-hydroxy-4-methoxyphenylethylamine accelerated the oxidation of both noradrenaline and 5-HT. Since demethylated metabolites of mescaline have been isolated by Musacchio and Goldstein (1967) from rats given this drug, it is possible that it is these metabolites which are the chemical species actually responsible for the observed central effects. In such a situation there should be a correlation between the central effects of the compound administered and the interaction of its demethylated metabolite with caeruloplasmin, but there would be no correlation between the central effects of the compounds and their effects on the enzyme. This point requires further experimental study. 

MAO inhibitors (MAOIs) These drugs (eg, phenelzine, tranylcypromine, isocarboxazid) are stmcturally related to amphetamines and are orally active. They inhibit both MAO-A (which metabolizes norepinephrine, serotonin, and tyramine) and MAO-B (which metabolizes dopamine). Tranylcypromine is the fastest in onset of effect but has a shorter duration of action (about a week) than do other MAO inhibitors (with durations of 2-3 weeks). In spite of these prolonged actions, the MAO inhibitors are given daily. These drugs are inhibitors of hepatic drug-metabolizing enzymes and cause many drug interactions. 

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