Monoamine oxidase inhibitors consequences

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

An explanation of the mode of action of the monoamine oxidase inhibitors in terms of their intervention in central transmission processes is difficult for several reasons. Monoamine oxidase is widely distributed in the body and some of the consequences of its inhibition may arise peripherally in the brain the enzyme participates in the inactivation of at least three substances (noradrenaline, dopamine and 5-hydroxytryptamine). Not all monoamine oxidase inhibitors have antidepressant activity but those that have may owe at least part of their activity to an action other than enzyme inhibition. 

Although the available evidence suggests that the antidepressant action of the monoamine oxidase inhibitors stems from their ability to increase the amount of noradrenaline in the brain, it should be remembered that many other compounds, including some depressants, also possess some ability to inhibit monoamine oxidase. Moreover, orally administered DOPA which, like the enzyme inhibitors, should also increase both the dopamine and the noradrenaline content of brain, is quite ineffective in relieving depression , though, as pointed out earlier, it does reverse sedation due to reserpine. Even if the effects of monoamine oxidase inhibitors are the consequence of... 

Reserpine is long-acting, and the postsynaptic neurons respond to the paucity of norepinephrine by "upregulating" (increasing) the number of receptors on the postsynaptic membrane. As a result, the postsynaptic terminal is supersensitive to direct sympathomi-metics. Consequently monoamine oxidase inhibitors (which prevent destruction of endogenous catecholamines such as norepinephrine and epinephrine) and direct sympathomimetics (Table 2.1 A) should be avoided in patients who have received reserpine. 

Health Canada s Natural Health Products Directorate (NHPD) has concluded that daily use by healthy adults of p-synephrine at up to 50 mg, or up to 40 mg in combination with up to 320 mg of caffeine, would generally result in a Type III risk classification. This classification is defined to mean that such use "is not likely to cause any adverse health consequences." On the other hand, NHPD determined that products that contain p-synephrine but lack certain cautionary statements, identified as "contraindicated in children, pregnancy, and breast-feeding, do not use if you are taking blood pressure medications (either hypertensives or antihypertensives), thyroid medications, sympathomimetics, or monoamine oxidase inhibitors," would be subject to a Type II risk classification (meaning "the use of, or exposure to, such a product may cause temporary adverse hedth consequences or where the probability of serious adverse health consequences is remote") (Maries 2011). 

Cesium exhibits marked effects on the nervous system, both peripherally and centrally. This may be the consequence of the purported interchangeability of cesium with other group I metals. Certainly cesium ions will increase the frequency of miniature end-plate potentials, thought to be due to the slow entry of cesium ions into the nerve terminal [32]. In the central nervous system, it seems that cesium can share the same receptor as glycine and exerts its effects by activating the same chloride channel as the inhibitory neurotransmitter, glycine [33]. Indeed, in consequence of this action, cesium has been implicated as a causative agent of some epileptiform seizures [34]. More recently, pretreatment of rats with cesium chloride, followed by administration of the monoamine oxidase inhibitor tranylcypramine, has been shown to enhance 5-hydroxytryptamine (5-HT) behavioral syndrome. This may be due to either an increased amount of 5-HT synthesis and/or release, or a direct enhancement of the postsynaptic action of 5-HT [34b]. 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

This was put forward in 1965 by J. Schildkraut and states that some, if not all, depressions are the consequence of an absolute or relative deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain (Schildkraut, 1965, p. 509). The evidence brought forward in support of this hypothesis was impressive (Table 4.2) because it covered both clinical and multifarious pharmacological findings. The antidepressant effect of imipramine and of the monoamine oxidase (MAO) inhibitors was attributed to the fact that these medicaments bring about an increased supply of functionally available catecholamines at the synapse ... 

FIGURE 6-4. The neurotransmitter receptor hypothesis of antidepressant action—part 3. The consequence of long-lasting blockade of monoamine oxidase (MAO) by an MAO inhibitor is that the neurotransmitter receptors are desensitized or down-regulated (indicated in the red circle). 

Stereotaxic application of drugs to feline caudate has established that the stereotyped behaviour produced by amphetamine, apomorphine, dopamine, and 3-methoxytyramine depends upon the presence of free dopamine receptors and dopamine [574], Caudate dopamine is metabolised by a monoamine oxidase isoenzyme [575], and elucidation of its structure and function might allow the use of a specific inhibitor as an adjunct to L-dopa therapy. Nigral melanin apparently utilises only dopa and dopamine in its formation, and the decreased melanin pigmentation in Parkinsonism may well be a consequence of the decreased availability of these substrates [576]. 

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