Inhibition of MAO

Hypertensive reaction resulting from release of noradrenaline by tyramine and other sympathomimetic amine as a consequence of irreversible inhibition of MAO-A. 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

RIMA Reversible, selective inhibition of MAO (causes Moclobemide ... 

Bladt S, Wagner FI. (1994). Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol. 7(suppl 1) S57-59. 

In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of dopamine and serotonin. 

Monoaminooxidase is a complex enzymatic system that is present in practically every organ that catalyzes deamination or inactivation of various natural, biogenic amines, in particular norepinephrine (noradrenaline), epinephrine (adrenaline), and serotonin. Inhibition of MAO increases the quantity of these biogenic amines in nerve endings. MAO inhibitors increase the intercellular concentration of endogenous amines by inhibiting then-deamination, which seems to be the cause of their antidepressant action. 

Maximum dose Do not use at daily doses exceeding those recommended (10 mg/day) because of the risks associated with nonselective inhibition of MAO. Pregnancy Category C. 

Other indirect sympathetic mechanisms are the inhibition of the extra neuronal uptake of noradrenaline (uptake 2) by corticosteroids and meta-nephrine and the inhibition of MAO for example by moclobemide or tranylcypromine. 

Moclobemide increases concentrations of serotonin and noradrenaline by means of reversible inhibition of MAO-A. Although moclobemide has an elimination half-life of only 1 hours its duration of action is considerably longer. 

Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B. However, it appears that inhibition of MAO-A, not MAO-B, is important to the antidepressant action of these agents. 

Haloallyl amines also have been studied as inhibitors of SSAO. The 2-aryl-3-haloallylamines proved to be potent irreversible inhibitors of rat aorta SSAO. Hydrophobic substituents on the aryl ring enhanced activity, while phenolic groups decreased activity [78]. The MAO B selective ( )-2-(3, 4 -dimethoxyphe-nyl)-3-fluoroallylamine (22d) inhibited rat SSAO in vascular and brown adipose tissues and was selective relative to inhibition of MAO A [79]. MDL 72974A (25) is a potent irreversible inhibitor of both MAO B and SSAO with a 190-fold lower affinity for MAO A [80]. 

Binding constants of several fluorinated and nonfluorinated analogues and corresponding diastereomers of the general structure A have also been determined in order to study the influence of the fluorine moiety and the stereochemical requirements on the inhibition of MAO A and B (Table 2) [92],... 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

As discussed above, many cyclopropylamines are good inhibitors of MAOs. In addition, as discussed in Section 3.2, fluorine substitution had substantial effects on the inhibition of MAOs by such analogues as allylamines. We undertook a broadly based study of the effects of fluorine substituted on the cyclopropyl ring of cyclopropyl amines on potency and selectivity of amine oxidase inhibition. In addition to effects on amine pKg and lipophilicity, we expected additional consequences resulting from altered geometry and ring strain due to the presence of fluorine. 

Nicotine, 4 phenylpyridine, and hydrazine, administered to mice, prevented the decrease in dopamine metabolite levels induced by MPTP, but there was no significant effect on dopamine levels. The compounds did not inhibit monoamine oxidase (MAO) activity in cerebral tissue in vivo. In vitro, an extract produced significant inhibition of MAO A and B activities in the... 

Figure 7.53 Postulated mechanism for the inhibition of MAOs by fluoroallyl amines.

A detailed study of the inhibition of MAOs by fluorophenyl cyclopropyl amines shows that the presence of fluorine has very important effects on this inhibition. While some of the regioisomers are inhibitors of the CAO (copper-containing amine oxidase), some other ones, such as 2-fluoro-l-arylcylopro-pyl amines, are excellent selective and irreversible inhibitors of MAO A. In this latter case, the nonfluorinated parent compound is a poor inhibitor of MAO B (Figure 7.55). ° " ... 

Figure 7.54 Schematic representation of the inhibition of MAOs by /i-fluoromethylene tyrosines.

Safinamide is in Phase 111 clinical trials for Parkinson disease. The molecule possesses multiple mechanisms of action it combines inhibition of dopamine uptake and potent, selective, and reversible inhibition of MAO-B, sodium (Na" ") channel blockage, and calcium channel modulation, while being devoid of a MAO-A inhibitory effect (Figure 8.37). 

The inhibition of MAO enzymes increases the concentrations of these neurotransmit-ters at storage sites throughout the CNS. Side effects of MAOIs include hypotensive effects from the inhibition of central vasomotor centers and cholinergic effects. 

As a class, MAOIs inhibit one or both MAO-A and MAO-B, resulting in elevated levels of neurotransmitters and other biogenic amines. Specific MAOIs can be subdivided on the basis of selectivity for inhibition of MAO-A or MAO-B and the reversibility of the enzyme-drug bond. Given concerns about adverse events associated with irreversible bonding and a desire to specifically target CNS neurotransmitter function, pharmaceutical development of MAOIs has focused on selectivity for MAO-A and reversibility. 

Optimism regarding the impact of selective inhibition of MAO-B on dopamine led to trials of selegiline... 

Inhibition of MAO can cause severe interactions with other drugs, as detailed in the Hypertensive Crisis and Serotonin Syndrome subsections earlier in this section. A list of drugs that interact with the nonselective MAOIs is provided in Table 2-5. 

Selegiline is an irreversible but relatively selective inhibitor of MAO-B. An oral preparation is currently marketed as a treatment for Parkinson s disease. An oral dose produces meaningful inhibition of MAO-B but not MAO-A. The concept behind the transdermal patch is to preferentially deliver more selegiline to the brain than to the liver such that meaningful inhibition of both MAO-A and MAO-B is achieved in the brain but only MAO-B inhibition is achieved in the liver. The... 

Only minimal information is available about the pharmacokinetics of the traditional MAOIs (e.g., phenelzine, tranylcypromine) ( 308). Such data are probably less critical for these versus other antidepressants, because MAOIs are consumed by their mechanism of action (i.e., irreversible inhibition of MAO by covalently binding to the enzyme). This mechanism accounts for the fact that traditional MAOIs have half-lives of only 2 to 4 hours, but their effects persist for an extended period because of their irreversible inactivation of their target. These MAOIs undergo presystemic or first pass degradation, and, thus, genetic or acquired alterations in this metabolism could alter their bioavailability and hence their effects. 

Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatr Neurol 1994 7(suppl 1) S54-S56. 

Inhibition of MAO types A+B and thus reduce metabolism Isocarboxazid of 5-HT and NA Phenelzine... 

These drugs are best avoided in patients with cerebrovascular, cardiovascular and hepatic disorders. Some sympathomimetic effects may occur, mainly mild tremor and occasionally cardiac arrhythmias. Apparent anticholinergic effects may also occur but these are the result of sympathetic potentiation in tissues with dual cholinergic/adrenergic innervation, e.g. pupil. Sympatholytic effects can also occur, principally postural hypotension, because of synthesis of relatively inactive false transmitters, e.g. octopamine, in nerve terminals following inhibition of MAO and activation of alternative metabolic pathways. 

Hyperpyrexia and hypertension have been observed with the use of pethidine and MAO inhibitors. Pethidine is the opioid most commonly associated with an adverse reaction with MAOIs. Although only a small proportion of patients taking MAOIs will react adversely to pethidine, there is no sure way of predicting those in whom the combination could produce severe, life-threatening reactions. These can present in two distinct forms. The excitatory form is characterised by sudden agitation, delirium, headache, hypotension or hypertension, rigidity, hyperpyrexia, convulsions and coma. It is possibly caused by an increase in cerebral 5-HT concentrations due to inhibition of MAO. This is potentiated by pethidine, which blocks neuronal uptake of 5-HT. The depressive form, which is frequently severe and fatal, presents as respiratoiy and cardiovascular depression and coma. It is the result of a reduced breakdown of pethidine due to the inhibition of hepatic /V-demethylase by MAOIs, leading to accumulation of pethidine. The risk of adverse reactions to pethidine may be less likely with the newer, specific MAO-A inhibitors. Interactions with other opioids, such as morphine and pentazocine, have been reported, but are less common. Other opioids appear to be safe in combination with MAOIs, with the possible exception of phenoperidine, which is metabolised to pethidine, norpethidine and pethidinic acid. 

It thereby also metabolizes the amine most closely linked to control of blood pressure (norepinephrine). The B form is thought to convert some amine substrates, called protoxins, into toxins that may cause damage to neurons. Because of these observations, MAO A inhibition is linked both to antidepressant action and to the troublesome hypertensive side effects of the MAO inhibitors. Inhibition of MAO B is linked to prevention of neurodegenerative processes, such as those in Parkinson s disease. 

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