Noradrenaline MAOIs

By maintaining low concentrations of cytoplasmic noradrenaline, MAO will also regulate the vesicular (releasable) pool of transmitter. When this enzyme is inhibited, the amount of noradrenaline held in the vesicles is greatly increased and there is an increase in transmitter release. It is this action which is thought to underlie the therapeutic effects of an important group of antidepressant drugs, the MAO inhibitors (MAOIs) which are discussed in Chapter 20. 

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

Synergy of unwanted pharmacological effect ginseng and its products will inhibit the central nervous system (CNS) when they are applied with luminal, chloral hydrate, or ephedrine, which can increase the release of dopamine, noradrenaline, and serotonin in the CNS thus inducing a hypertensive crisis if monoamine oxidase inhibitors (MAOIs) are given simultaneously. 

MAOI non-selective monoamine oxidase (A/B) inhibitors RIMA reversible inhibitor of monamine oxidase type A SSRI selective serotonin (5-HT) reuptake inhibitors SNRI serotonin/noradrenaline reuptake inhibitor SNARI selective noradrenaline (NA) reuptake inhibitor NA = 5-HT — DA potency of the drug is very similar in raising the level of both (or all three) monamines NA > 5-HT more selective for NA 5-HT>NA more selective for 5-HT NA increases the release of NA. 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

The main limitation to the clinical use of the MAOIs is due to their interaction with amine-containing foods such as cheeses, red wine, beers (including non-alcoholic beers), fermented and processed meat products, yeast products, soya and some vegetables. Some proprietary medicines such as cold cures contain phenylpropanolamine, ephedrine, etc. and will also interact with MAOIs. Such an interaction (termed the "cheese effect"), is attributed to the dramatic rise in blood pressure due to the sudden release of noradrenaline from peripheral sympathetic terminals, an event due to the displacement of noradrenaline from its mtraneuronal vesicles by the primary amine (usually tyramine). Under normal circumstances, any dietary amines would be metabolized by MAO in the wall of the gastrointestinal tract, in the liver, platelets, etc. The occurrence of hypertensive crises, and occasionally strokes, therefore limited the use of the MAOIs, despite their proven clinical efficacy, to the treatment of atypical depression and occasionally panic disorder. 

Many antidepressant drugs have pronounced effects on sleep. Several tricyclic compounds (amitriptyline and others) have sedative actions while others (imipramine and others) are less sedative or even stimulant. Monoamine oxidase inhibitors (MAOIs) have central stimulant effects and may cause insomnia. Specific serotonin reuptake inhibitors (SSRls) and combined serotonin, noradrenaline reuptake inhibitors (SNRIs) can also cause insomnia. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

Tyramine acts as an indirect sympathomimetic to cause release of catecholamines from nerve terminals. It is present in a number of foods mature cheese, yeast extracts, some red wines, hung game, pickled herrings, broad bean pods. Normally, MAO-A in the intestinal mucosa will metabolise tyramine absorbed from the gut. In patients on the older MAOls, considerable amounts of tyramine will enter the circulation and this will lead to increased release of catecholamines stored in nerve terminals because the MAOI prevents their metabolism. For patients on RIMA drugs, high concentrations of tyramine can compete for MAO-A, thus mitigating some of the effects, and MAO-B is still available to metabolise noradrenaline (norepinephrine). MAO-B, however, has relatively much less effect on 5-HT and thus 5-HT function is still enhanced. 

Newer MAOI drugs are selective for the MAO-A subtype of the enzyme, and are less likely to interact with foods or other drugs. Monoamine oxidase (MAO) inactivates monoamine substances, many of which are, or are related to, neurotransmitters. The central nervous system mainly contains MAO-A, whose substrates are adrenaline (epinephrine), noradrenaline (norepinephrine), metanephrine, and 5-hydroxyti7ptamine (5-HT), whereas extra-neuronal tissues, such as the liver, lung, and kidney, contain mainly MAO-B which metabolises p-phenylethylamine, phenylethanolamine, o-tyramine, and benzylamine. 

Monoamine oxidase inhibitors (MAOIs), which were amongst the first antidepressant drugs to be used clinically. They affect one or both of the brain monoamine oxidase enzymes that play a role in the metabolism of serotonin, noradrenaline, dopamine and adrenaline. MAOIs inhibit breakdown of the neurotransmitters important in determining mood, which results in the antidepressant effect. 

Q14 MAOIs, such as phenelzine and isocarboxazid, affect the sympathetic nervous system by inhibiting one or both forms of brain monoamine oxidase. Their sympathomimetic effects can produce a feeling of well-being and increased energy, which is helpful for depressed patients. However, psychosis may occur in a susceptible individual or may follow over-administration of these agents. An increase in sympathomimetic action (such as occurs with use of amphetamines, which increase the release of noradrenaline) can result in a lethal hypertensive crisis. In addition, a hypertensive crisis can also be initiated if the patient consumes a diet rich in amines foods with a high amine content include cheese, pickles, broad beans and wine. 

MAOIs increase the availability of noradrenaline and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal. The older MAOIs, phenelzine. 

Interactions. With nonselective monoamine oxidase inhibitors (MAOI), the monoamine dopamine formed from levodopa is protected from destruction it accumulates and also follows the normal path of conversion to noradrenaline (norepinephrine), by dopamine (J-hydroxylase severe hypertension results. The interaction with the selective MAO-B inhibitor, selegiline, is possibly therapeutic (see below). Tricyclic antidepressants are safe. Levodopa antagonises the effects of antipsychotics (dopamine receptor blockers). Some antihypertensives enhance hypotensive effects of levodopa. Metabolites of dopamine in the urine interfere with some tests for phaeochromocytoma, and in such patients it is best to measure the plasma catecholamines directly. 

MONOAMINE-OXIDASE-INHIBITORS(MAOIs) acton monoamine-oxidase (MAO) enzymes that are involved in the degradation of monoamines in the peripheral and central nervous system. Monoamine oxidase occurs within cells bound to the surface of the mitochondria. It is found not only within monoaminergic neurons, but also in the liver and intestinal epithelium. The enzyme converts amines to their corresponding aldehydes, which in the periphery are converted to their carboxylic acids by aldel e dehydrogenase. Neurotransmitters degraded by monoamine oxidase include dopamine. 5-hydnngrtryptamine and noradrenaline. 

Sympathomimetic decongestants interact with monoamine oxidase inhibitors (MAOIs), preventing the breakdown of noradrenaline and increasing... 

Evidence accumulated in 1978 for a catecholamine receptor supersensitivity theory of depression. 8 The therapeutic action of antidepressants may be due to delayed post-synaptic changes in receptor sensitivity, rather than to acute events like uptake. Various drugs, including TCA, mianserin, viloxazine and iprindol, as well as electroconvulsive therapy (ECT), but not selective 5-HT uptake inhibitors, caused central alpha-adrenoceptor subsensitivity in rats as measured by noradrenaline (NA)-associated adenylate cyclase or by receptor binding. In vivo, the effects were associated with chronic but not acute treatment, paralleling the clinical effects. MAOI may cause similar effects on chronic but not acute treatment. , 24-27 Brain NA turnover in rats was decreased by chronic desipramine and other TCA, but unaffected by iprindol and increased by mianserin.3,28... 

Monoamine oxidase inhibitors (MAOIs) are drugs that irreversibly inhibit the action of the enzyme monoamine oxidase. Monoamine oxidase exists in two forms MAO-A and MAO-B. MAO-A is the enzyme preferentially responsible for degrading serotonin and noradrenaline. Inhibition of this enzyme allows the concentration of these monoamines to increase in the brain, thereby producing an antidepressant effect. 

The concurrent use of MAOIs is contraindicated by the manufacturers of indoramin. This was included in the datasheet at the time indoramin was first licensed, and was based on a theoretical suggestion that the effects of noradrenaline (norepinephrine) may be potentiated by indoramin, leading to vasoconstriction with a possible increase in blood pressure. However, the pharmacology of these drugs suggests just the opposite, namely that hypotension is the more likely outeome. (Note that the hypertensive effects of noradrenaline (norepinephrine) may be treated with a non-selec-tive alpha blocker such as phentolamine.) The manufaeturers are not aware of any reported interactions between indoramin and MAOIs. Note that the MAOIs are not contraindieated with any of the other alpha bloek-... 

After 5 to 10 days of use furazolidone has MAO-inhibitory activity about equivalent to that of the non-selective MAOIs. The concurrent use of furazolidone with indirectly-acting sympathomimetic amines (amfetamines, phenylpropanolamine, ephedrine, etc.) or with tyramine-rich foods and drinks may be expected to result in a potentially serious rise in blood pressure. However, direct evidence of accidental adverse reactions of this kind does not seem to have been reported. The pressor effects of noradrenaline (norepinephrine) are unchanged by furazolidone. 

After 6 days of treatment with furazolidone 400 mg daily, the pressor responses to tyramine or dexamfetamine in 4 hypertensive patients had inereased two to threefold, and after 13 days by about tenfold. These responses were about the same as those found in 2 other patients taking the MAOI pargyline. The MAO-inhibitory activity of furazolidone was confirmed by measurements taken on jejunal specimens. The pressor effects of noradrenaline (norepinephrine) were unchanged by furazolidone. ... 

The manufaeturers eontraindieate the use of sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine, adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine, dob-utamine) with linezolid unless there are faeilities available for close observation of the patient and monitoring of blood pressure. Some indirectly-aeting sympathomimetics occur in cough and cold remedies, whieh can be bought without prescription. To keep in line with the manufaeturers recommendations, patients should be told to avoid these preparations. However, it should be said that the evidenee available indicates that blood pressure rises are unlikely to be of the proportions seen with the antidepressant MAOIs, which result in hypertensive crises. Consider also MAOIs or RIMAs + Sympathomimetics Indirectly-acting , p.l 147. 

Broad bean (Vidafaba) pods contain dopa, which is enzymatically converted in the body, firstly to dopamine and then to noradrenaline, both of which are normally broken down by monoamine oxidase. In the presence of an MAOI this breakdown is suppressed, which means that the total levels of dopamine and noradrenaline are increased. Precisely how this then leads to a sharp rise in blood pressure is not clear, but either dopamine or noradrenaline, or both, directly or indirectly stimulate the alpha-receptors of the eardiovascular system. 

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