Selegiline moclobemide

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). 

Isocarboxizid, phenelzine, selegiline, tranylcypromine, moclobemide, clorgiline, and linezolid... 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

These mediators probably play significant roles in CNS functions consistent with the stimulant effects of MAO inhibitors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcypromine is used to treat particular forms of depressive illness as a covalently bound suicide substrate, it causes long-lasting inhibition of both MAO isozymes, (MAOa, MAOb). Moclobemide reversibly inhibits MAOa and is also used as an antidepressant. The MAOb inhibitor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

Adrenaline and noradrenaline are unstable in aqueous solution where they are subjected to spontaneous oxidation. In vivo this mechanism is only relevant under pathophysiological conditions of an catecholamine excess, since two enzymes, the catechol-O-methyltransferase (COMT) and the monoamineoxidase (MAO), inactivate physiological amounts of the transmitters. There are at least two subtypes of the enzyme MAO, A and B, which can be inhibited selectively for therapeutic purposes, for example by moclobemide and selegiline. 

Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the non-hydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects. 

MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible. Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs. Moclobemide is a reversible and selective inhibitor of MAO-A but is not available in the USA. Moclobemide can be displaced from MAO-A by tyramine, and this mitigates the risk of food interactions. In contrast, selegiline is an irreversible MAO-B-specific agent at low doses. Selegiline is useful in the treatment of Parkinson s disease at these low doses, but at higher doses it becomes a nonselective MAOI similar to other agents. 

From the evidence available to date, the reversible, short-acting MAO inhibitor moclobemide, which is available in several countries (but not the USA), appears to be relatively free of this interaction. (The selective MAO-B inhibitor selegiline loses selectivity at antidepressant dosage. Because its action is on the enzyme that metabolizes dopamine, it is most useful in the treatment of Parkinson s disease [Chapter 28 Pharmacologic Management of Parkinsonism Other Movement Disorders].)... 

Patients taking moclobemide can usually eat a normal diet, since there is no significant potentiation of tyramine. However, the combination in high doses (20 mg or more) of selegiline and moclobemide potentiates the pressor effects of tyramine (presumably because of simultaneous inhibition of both MAO type A and MAO type B), and a tyramine-free diet is needed if the two drugs are used together (SEDA-20, 6). 

Isocarboxazid (Marplan) Moclobemide (Aurorix, Manerix, Moclodura ) Phenelzine (Nardil) Tranylcypromine Selegiline (Selegiline, Eldepryl)... 

Monoamine oxidase (MAO) enzymes have an important function in modulating the intraneuronal content of neurotransmitter. The enzymes exist in two principal forms, A and B, defined by specific substrates some of which cannot be metabolised by the other form (Table 20.3). The therapeutic importance of recognising these two forms arises because they are to some extent present in different tissues, and the enzyme at these different locations can be selectively inhibited by the individual inhibitors moclobemide for MAO-A (used for depression, p. 379) and selegiline for MAO-B (Table 20.3). 

All available monoamine oxidase (MAO) inhibitors (excepting moclobemide, toloxatone, brofaromine, and selegiline) act via a suicide mechanism, by causing long-lasting, irreversible, competitive inhibition of... 

Most MAOIs are irreversible and the effects take weeks to stabilize. Chemically, they fall into a number of groups, including hydrazines, such as pheneizine and iproniazid, propargylamines, such as pargyline, chlorgyline and selegiline, and cyclopropylamines, such as tranylcypromine. A reversible inhibitor that may be safer under some circumstances is moclobemide. The use of MAOIs has declined and tricyclics and the SSRIs are being used more. See antidepressants. 

Clinically important, potentially hazardous interactions with alprazolam, amphetamines, astemizole, clarithromycin, clozapine, desipramine, dexibuprofen, dextroamphetamine, diethylpropion, droperidol, duloxetine, erythromycin, haloperidol, imipramine, isocarboxazid, linezolid, lithium, MAO inhibitors, mazindol, meperidine, methamphetamine, midazolam, moclobemide, nortriptyline, phendimetrazine, phenelzine, phentermine, phenylpropanolamine, phenytoin, pimozide, pseudoephedrine, selegiline, serotonin agonists, sibutramine, St John s wort, sumatriptan, sympathomimetics, tramadol, tranylcypromine, trazodone, tricyclic antidepressants, troleandomycin, tryptophan, zolmitriptan... 

Clinically important, potentially hazardous interactions with acyclovir, alcohol, amphetamines, barbiturates, CNS depressants, fluoxetine, furazolidone, general anesthetics, glycopyrrolate, glycopyrronium, isocarboxazid, linezolid, lithium, MAO inhibitors, moclobemide, phenelzine, phenobarbital, phenothiazines, rasagiline, ritonavir, selegiline, sibutramine, SSRIs, tranquilizers, tranylcypromine, tricyclic antidepressants, val acyclovir... 

This concept has led to market isoenzyme selective inhibitors, that is, monoamine oxidase (MAO) inhibitors (moclobemide for MAO-A as an antidepressive drug, selegiline for MAO-B in Parkinson disease), selective inhibitors for various cyclic nucleotide phosphodiesterases (sildenafil for PDE5), and selective cyclooxygenase inhibitors (celecoxib for cox2). 

Monoamine Oxidase Inhibitors Isocarboxazid, Phenelzine, Tranylcypromine, Selegiline, Moclobemide... 

MAOIs can be classified into two groups the irreversible (older) MAOIs such as Parnate (tranylcypromine) and Nardil (phenelzine), and the reversible (newer) drugs such as Manerix (moclobemide) and Deprenyl (selegiline). Older MAOIs have more side effects associated with them since their action is less specific than newer MAOIs. 

MAOIs are classified as selective and non-selective and as reversible and irreversible. The main non-selective MAOIs include isocarboxazid, nialamide, tranylcypromine, and phenelzine (all irreversible). The selective MAOIs are classified as MAO-A and MAO-B inhibitors. The MAO-A selective inhibitors include befloxatone, cimoxatone, moclobemide, and toloxatone (all reversible). The MAO-B selective inhibitors include pargyline and selegiline (deprenyl) (all irreversible). 

MAOIs BETA-2 AGONISTS t occurrence of headache, hypertensive episodes. Unlikely to occur with moclobemide and selegiline Due to impaired metabolism of these sympathomimetic amines because of inhibition of MAO. Moclobemide is involved in the breakdown of serotonin, while selegiline is mainly involved in the breakdown of dopamine Be aware. Monitor BP closely... 

The UK manufacturer contraindicates the concurrent use of linezolid with or within 2 weeks of taking any other drug that inhibits MAO-A or MAO-B. They specifically name the non-selective MAOIs isocarboxazid and phenelzine, the RIMA, moclobemide, and the MAO-B inhibitor, selegiline. Linezolid has reversible non-selective MAO-inhibitory activity, and this warning is based on the sometimes serious reactions that have occurred when non-selective MAOIs are given sequentially (see MAOIs + MAOIs or RIMAs , p.1137) or MAOIs are given with MAO-B inhibitors, see MAO-B inhibitors + MAOIs or RIMAs , p.692. 

In a single dose study, there was no adverse effect on heart rate or blood pressure when entacapone was given with moclobemide (a RIMA), but caution is recommended until further clinical experience is gained. The COMT inhibitors may be used with the MAO-B inhibitors (such as selegiline). However, the manufacturers of entacapone and tolcapone contraindicate concurrent use of non-selective MAOIs or a combination of both a RIMA and a MAO-B inhibitor. 

Marked orthostatic hypotension has been seen in two patients taking iproniazid or tranylc3 romine/trifluoperazine when given sel line. When the RIMA moclobemide is given with selegiline, restriction of dietary tyramine is necessary, and there may be an increased risk of hypotensive reactions. Some manufacturers of MAO-B inhibitors contraindicate the concurrent use of MAOIs or RIMAs. 

In practical terms this means that patients taking moclobemide with selegiline should be given the same dietary restrictions for tyramine-rich foods and drinks (see tyramine-rich drinks , (p.l 151) and tyramine-rich foods , (p.l 153)), that relate to the non-selective MAOIs such as phenelzine and tranylcypromine. However, because of the potential risks the manufacturer of moclobemide contraindicate this combination. On the basis of work done on the pig it is suggested that if selegiline is replaced by moclobemide, the dietary restrictions can be relaxed after a wash-out period of about 2 weeks. If switching from moclobemide to selegiline, a wash-out period of 1 to 2 days is sufficient. ... 

Korn A, Wagner B, Moritz E, Dingemanse J. T3n amine pressor sensitivity in healthy subjects during combined treatment with moclobemide and selegiline. EurJ Clin Pharmacol (1996) 49, 273-8. 

Dingemanse J,KneerJ, WaUnofer A, KettlerR,ZurcherG, Koulu M, Korn A. Pharmacokinetic-pharmacodynamic interactions between two selective monoamine oxidase inhibitors moclobemide and selegiline. Clin Neuropharmacol (1996) 19, 399-414. 

Jansen Steur ENH, Ballering LAP. Moclobemide and selegiline in the treatment of depression in Parkinson s disease. J Neurol Neurosurg Psychiatry (1997) 63, 547. 

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