Monoamine oxidase inhibitors available drugs

The monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut. 

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

Monoamine Oxidase Inhibitors (MAOIs). Early studies also evaluated the effectiveness of the MAOl phenelzine. Phenelzine, relative to TCAs, provided greater benefit for PTSD however, its usefulness is limited by its potential for drug and food interactions. A recent open label study suggests that the reversible MAOI moclobemide might be helpful for PTSD. It is not available in the United States. 

Monoamine oxidase inhibitors (MAOIs) are useful as thymoleptic (antidepressant) drugs, especially since the action of some of these agents is very rapid, as compared to the lag period of days or even weeks shown by tricyclic antidepressants. All MAOIs act by increasing the available concentration of the neurotransmitters NE and 5-HT which, because they are not metabolized, accumulate in the synaptic gap and exert an increased postsynaptic effect. The drugs show hypotensive activity as a side effect, and some MAOIs are used as hypotensive drugs. 

EXTENSIONS AND COMMENTARY In the 1960 s there was quite a bit of interest in a couple of pharmaceutical houses with the indole analogues of amphetamine. Both the alpha-methylated tryptamine (this compound, a-MT) and the alpha-ethylated homologue (a-ET, see its separate recipe) were found to be effective monoamine oxidase inhibitors, and both were clinically studied as potential antidepressants. The ethyl compound became a commercial drug, offered by the Upjohn Company as Monase, but now is considered to be without medical use and is a Schedule I drug. It is interesting that this methyl compound, a-MT was also a medically available antidepressant in the Soviet Union in the 1960 s and was sold under the name of Indopan, in 5 and 10 milligram tablets. 

Several drug groups are available for the treatment of major (endogenous) depression. These include the selective serotonin reuptake inhibitors (SSRIs), the tricyclic agents (TCAs), a group of heterocyclic antidepressants, and the monoamine oxidase inhibitors (MAOIs). 

Section B (Fig. 17) shows some commonly used drugs which are electroactive. The a-methyltryptamine was detected at + 0.8 V by Marsden (1980) in 5-HT studies. Several monoamine oxidase inhibitors are electroactive, but there is so far no evidence that they can be detected in vivo and, even if they are, it is at potentials sufficiently positive not to interfere with most studies. Chlorpromazine and haloperidol have solution Ep values about + 0.6 V and + 0.7 V, respectively. Clozapine oxidizes at about + 0.4 V. Since neuroleptics (and other drugs) are extensively metabolized by the time they appear in significant concentrations in the CNS, the potentials of the parent compounds may not be too relevant—but no data are available for metabolites. In any event, there is no evidence that any of these drugs are detected in CNS voltammetry. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

Monoamine oxidase (MAO) is a mitochondrial enzyme found in neural and other tissues, such as the gut and liver. In the neuron, MAO functions as a safety valve to oxidatively deaminate and inactivate any excess neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. Three MAO inhibitors are currently available for treatment of depression phenelzine [FEN el zeen], isocarboxazid [eye soe kar BOX a zid], and tranylcypromine [tran ill SIP roe meen] no one drug is a prototype. Use of MAO inhibitors is now limited because of the complicated dietary restrictions required of patients taking MAO inhibitors. 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

Monoamine oxidases are integral outer mitochondrial membrane proteins that catalyze the oxidative deamination of primary and secondary amines as well as some tertiary amines. MAO occurs as two enzymes, MAO-A and MAO-B, which differ in substrate selectivity and inhibitor sensitivity (Abell and Kwan, 2001 Edmondson et al., 2004 Shih et al., 1999). A number of MAO inhibitors have been developed for clinical use as antidepressants and as neuroprotective drugs. Clinically used drug substances include, among others, moclobemide, a relatively selective reversible MAO-A inhibitor, and L-deprenyl, an irreversible selective inhibitor of MAO-B. In vitro, clorgyline and L-deprenyl are used as selective irreversible inhibitors of MAO-A and B, respectively. (Note For in vitro studies using irreversible inhibitors, preincubation of the irreversible inhibitor with the enzyme prior to initiation of the substrate reaction is required for optimal inhibition.) Expressed MAO-A and MAO-B are not readily available via commercial resources however, MAO-A and MAO-B have been evaluated and are active in subcellular fractions. While monoamine oxidases are located in the mitochondria, many microsomal preparations are contaminated with monoamine oxidases during the preparation of the microsomal subcellular fraction and thus microsomes are sometimes used to evaluate monoamine oxidase activity in combination with selective inhibitors. 

Many noncyclic antidepressants are now available, including trazodone (Desyrel l), nefazodone (Serzone ), fluoxetine (Prozac ), sertraline (Zolotf ), citalopram (Celexa ), escitalopram (Lexapro ), paroxetine (Paxil ), tluvoxamine (Luvox ), venlafaxine (Effexor ), and bupropion (Wellbutrin ). Bupropion is also marketed under the brand name Zyban tor smoking cessation. Mirtazapine (Remeron ), a tetracyclic antidepressant, has recently become available. In general, these drugs are much less toxic than the tricyclic antidepressants (see p 90) and the monoamine oxidase (MAO) inhibitors (p 269), although serious effects such as seizures and hypotension occasionally occur. Noncyclic and tricyclic antidepressants are described in Table 11-7. 

Some of the newer and more recently developed drugs with MAO inhibitory activity (see Table 32.1 , (below)) interact to a lesser extent than the older MAOIs. This is because they are largely selective. One group of these selective inhibitors targets MAO-A, and are relatively rapidly reversible inhibition of this enzyme is responsible for the antidepressant effect. These selective MAO-A inhibitors (moclobemide, toloxatone) have been given the acronym RIMAs (Reversible Inhibitors of Monoamine oxidase A). They leave MAO-B largely uninhibited so that there is still a metabolic pathway available for the breakdown of amines, such as... 

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]. 

---