Selegiline Monoamine oxidase inhibitors

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. 

Accordingto the FDA-approved prescribing information for the transdermal selegiline patch, patients receiving the 6 mg/24 hour dose are not required to modify their diet. However, patients receiving the 9 or 12 mg/24 hour dose are still required to follow the dietary restrictions similar to the other monoamine oxidase inhibitors (MAOIs). 

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. 

Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used for the treatment of Parkinson s disease (see Chapter 28). 

Banisterine from Banisteria caapi and Nicotiana tabacum is a monoamine oxidase inhibitor that is similar pharmacologically to selegiline (deprenyl), which is used in the treatment of Parkinson s disease. 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

Concomitant use of some opioid analgesics, such as pethidine or dextropropoxyphene, with the selective monoamine oxidase inhibitors selegiline and moclobe-mide can enhance their nervous system toxicity (71). 

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. 

Lefebvre H, Noblet C, Moore N, Wolf LM. Pseudo-phaeochromocytoma after multiple drug interactions involving the selective monoamine oxidase inhibitor selegiline. Clin Endocrinol (Oxf) 1995 42(l) 95-98 discussion 98-99. 

Because of undesirable side effects associated with monoamine oxidase inhibitor therapy (see section 2.3.2), pharmaceutical companies nearly abandoned research on new analogs in the 1960s. The early MAO inhibitors were nonselective and irreversible. Today, efforts toward the development of monoamine oxidase inhibitors are focused on selective MAQA or MAOB inhibitors. Selective MAOB inhibitors are being examined in the treatment of, for example, schizophrenia, Alzheimer s disease, and Parkinson s disease. MAO-B inhibitors might be effective in the treatment of depression, but relatively little woik has been done in this area. Selegiline... 

To inhibit Aj8 aggregation into amyloid is to prevent misfolding of soluble AjS. Once the misfoldingtook place the aggregation is only a matter of time and far more difficult to control (174). So far only nicotine (30,Fig. 13.9) and melatonin (31)appear to be affecting the conformation of soluble AjS (175-177). Antioxidants, such as antituberculosis antibiotic ri-fampicin (32) or a-tocopherol, were reported to inhibit aggregation and neurotoxicity of AjS in vitro (178-180). A monoamine oxidase inhibitor, selegiline (33, Fig. 13.9), may also be... 

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

Selegiline - monoamine oxidase-B inhibitor Parkinson s disease... 

Monoamine oxidase inhibitors are classified into A and B types. Monoamine oxidase A preferentially uses serotonin and norepinephrine as substrates and is inhibited by chlor-gyline and harmaline. Monoamine oxidase B preferentially uses dopamine and is inhibited by selegiline (see also Figures 37 and 87). 

Meperidine has a strong adverse reaction when given to patients receiving a monoamine oxidase inhibitor. This drug interaction has been seen recently in patients with Parkinson s disease taking the monoamine oxidase-selective inhibitor selegiline (Eldepryl). 

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. 

Early antidepressant medications were called tricyclic antidepressants (TCA), exemplified by dothiepin and amitriptyline. However, there are toxicity issues with these medications. The next generation of antidepressants was the monoamine oxidase inhibitors (MAOIs). As their name implies, they inhibit the monoamine oxidase enzyme thereby inhibiting the oxidation of monoamines such as serotonin that act as neurotransmitters. Examples include selegiline (available in transdermal patch form as Emsam , Somerset... 

Monoamine Oxidases and their Inhibitors. Figure 2 Structures of MAO inhibitors. In the top row, the structural similarity between selegiline/L-deprenyl and methamphetamine is shown. Below are the aminoindan series of propargylamine compounds such as rasagiline. Next, the bifunctional MAO and cholinesterase inhibitors (ladostigil) and lastly, the iron chelator-MAO inhibitors. 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

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. 

---