Monoamine oxidase inhibitors limitations

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). Controlled trials comparing the M AOl phenelzine to clomipramine or fluoxetine have produced mixed results. Given the limited data regarding any efficacy of MAOIs in the treatment of OCD coupled with their potentially dangerous interactions, we cannot recommend MAOIs in the treatment of OCD until other approaches have been tried. 

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). The MAOls work in a unique fashion by blocking the activity of an enzyme that degrades each of three key brain transmitters norepinephrine, dopamine, and serotonin. These widespread effects on several brain transmitter systems make the MAOls a potentially very effective class of medications for a variety of disorders. A few small studies have evaluated the usefulness of the MAOls in the treatment of BPD and found them moderately helpful for the impulsivity associated with this illness. Unfortunately, the requirements for strict dietary restrictions due to a risk of hypertensive crisis severely limit the usefulness of MAOls in the treatment of BPD. These restrictions are a particular concern when treating patients who have problems with impulsivity and are therefore likely to have difficulty maintaining the dietary regimen. For this reason, although they may theoretically be helpful, MAOls should only be used to treat BPD after other more easily tolerated medications have been tried and have failed. In the near future, so-called reversible MAOls that appear to avoid the need for diet restrictions may become available. If so, this will allow us to reconsider their use in the treatment of BPD. For more information regarding the use of MAOls, please refer to Chapter 3. 

In an early study, Insel et al. [1983b] compared the efficacy of CMI with that of clorgiline, a monoamine oxidase-A inhibitor, in a controlled crossover study of patients with OCD. Although CMl was effective, patients on clorgiline did not improve at all. Vallejo et al. [1992] conducted a controlled clinical trial of the efficacy of CMl and phenelzine in 30 patients with OCD. The authors reported improvement in both groups however, the lack of a placebo control and the small size of the study groups limit the applicability of these findings. Further studies on the therapeutic role of monoamine oxidase inhibitors in OCD, especially in OCD with comorbid panic disorder, are warranted. 

Although behavioral treatments for social phobia have been well studied, there are very limited data on its pharmacological management, b- Blockers (propranolol, atenolol) have been recommended, but available evidence indicates their effect may be no different than that of placebo ( 78). In a controlled study, the monoamine oxidase inhibitor (MAOl) phenelzine has been shown to be more effective than placebo (78, 79). Anecdotal reports have also described efficacy with alprazolam, clonidine, and fluoxetine, but systematic data are lacking (80, 81, 82 and 83). 

Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (K-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

From the existing literature, St. John s wort appears to be a safe and effective alternative in the treatment of depression. Tricyclic antidepressants and monoamine oxidase inhibitors can produce serious cardiac side effects, such as tachycardia and postural hypotension, and many unwanted anticholinergic side effects, including dry mouth and constipation. St. John s wort has proved to be free of any cardiac, as well as anticholinergic, side effects normally seen with antidepressant medications. Based upon limited studies, St. John s wort appears to be an acceptable alternative to traditional antidepressant therapy. 

Other advances in the field were antianxiety (or anxiol> tic) medications, such as meprobamate (which also was used as a muscle relaxant), and antidepressant medications, such as monoamine oxidase inhibitors (fvIAOls) and tricyclic antidepressants. Another drug that received renewed attention was LSD. Because of the psychotic-like effects produced by LSD, researchers used it to create a model psychosis to study (to date with limited success) possible etiological factors contributing to mental illness. They could also treat the LSD-created symptoms with psychotherapeutic drugs. 

The monoamine oxidase inhibitors are associated with a number of undesirable side effects including weight gain, postural hypotension, sexual dysfunction, and insomnia. The most serious side effect is the risk of tyramine-re-lated hypertensive crisis, often referred to as the "cheese effect," which can be fatal. To avoid this situation patients taking MAOIs must limit their tyramine intake, and the restrictive diet required to accomplish this leads to low patient compliance. A similar interaction occurs when switching patients from MAOI to SSRI therapy, and a minimum 2-week washout period before commencement of SSRI therapy is essential to allow MAO levels to return to normal. The therapeutic effects of the TCAs derive from their inhibition of serotonin and norepinephrine uptake, al-... 

Monoamine oxidase inhibitors (MAOIs), such as phenelzine, have been used in the management of refractory headache, but their complex adverse-effect profile limits their use to experienced prescribers. Strict adherence to a tyramine-free diet is necessary to avoid potentially life-threatening hypertensive crisis. 

Considerable interest has recently been aroused by reports that patients treated with monoamine oxidtise inhibitors may suffer severe hypertensive attacks after taking certain foods, notably cheese - , beans and extracts of yeast . Some of these attacks have proved fatal. The hypertensive crises arise as a result of pressor substances in the offending foods (such as tyramine in cheese) which are absorbed unchanged into the blood stream when intestinal and liver monoamine oxidase is inhibited . Some of the inhibitors (tranylcypromine is an example) also have sympathomimetic actions which will contribute to the hypertensive effect. The administration of sympathomimetic substances—such as adrenaline in a local anaesthetic—to patients treated with monoamine oxidase inhibitor also creates a dangerous situation. The possibility of hypertensive crises clearly constitutes a serious hazard of therapy with these enzyme inhibitors. In many instances their limited effectiveness would not justify the exposure of patients to these hazards. 

Glaxo Pharmaceuticals UK Limited. A study to determine whedier the pharmacokinetics, safety or tolerability of subcutaneously administered sumatriptan (6 mg) are altered by interaction with concurrent oral monoamine oxidase inhibitors. Data on file (Protocol C92-050),... 

Steric Parameters - The steric parameter, E, of Taft has been employed by Kutter and Hansch in the correlation of the molecular structure of some phenoxyethylcyclopropylamine monoamine oxidase inhibitors and diphenhydramine antihistamines with their activity. For the types of biological activity investigated it was found that the Taft Eg was more important in the correlation than was either the electronic parameter of Hammett, a, or the hydrophobic parameter of Hansch. Their results led Kutter and Hansch to conclude that the binding of substituent groups of moderate size into a macro-molecular pouch may well be, at least over a limited range, a continuous linear process. This would negate the all-or-none situation which sometimes arises from the "lock and key" theory of enzyme-substrate interaction. ... 

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...

During clinical studies of iproniazid (201) in the treatment of tuberculosis it was found to have a mood-elevating effect. It was later found to be an inhibitor of monoamine oxidase (MAO), the enzyme which oxidatively deaminates such neurotransmitters as noradrenaline and serotonin, and it was tried in the treatment of depression in 1957. Other MAO inhibitors were introduced later, most of them being hydrazine derivatives. Heterocyclic examples include isocarboxazid (202) and nialamide (203). They are toxic and cause dangerous hypertensive crises if food with a high tyramine content is eaten, and on this account their use is limited. 

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. 

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