Posted by ed_uk on May 20, 2005, at 19:31:02
In reply to tranylcypromine versus phenelzine, posted by ixus on May 20, 2005, at 16:56:10
Hi Ixie!
This info might be useful. It's certainly very interesting that MAOIs inhibit all those enzymes apary from MAO!!!
Irreversible Inhibitors of MAO
Inhibitors of MAO (MAOIs) are distinguished on the basis of their specificity for MAO-A and -B, as well as the reversibility of their inhibition (Table 3). The MAOIs currently in clinical use in the United States are all irreversible ('suicide') inhibitors characterized by site-specific covalent binding of MAO. Phenelzine and the putative active metabolite of isocarboxazid are derivatives of hydrazine, whereas pargyline and deprenyl are acetylenic agents. Both the hydrazine and the acetylenic agents bind to the flavin prosthetic group of MAO following their oxidation to reactive intermediates. The mechanism of action of the cyclopropylamine tranylcypromine is less certain but may involve initial formation of an imine by MAO, followed by reaction of a sulfhydryl group in the active center of the enzyme. Except for deprenyl, MAOIs currently in clinical use are nonselective with regard to both forms of the enzyme. Deprenyl, at doses up to 10 mg/day, selectively inhibits MAO-B; higher doses also inhibit MAO-A. Irreversible selective inhibitors of MAO-A, such as clorgyline, appear efficacious in the treatment of depression but are currently used only experimentally.
Oral absorption of the MAOIs is rapid. Inhibition is maximal within a few days, though antidepressant effects may be delayed by 2–3 weeks. Following withdrawal of the drug, the half-life of the disappearance of MAO inhibition is estimated in the rodent brain at 11–12 days for phenelzine and pargyline and 2.5 days for tranylcypromine. The half-life in human brain is likely to be longer. Studies using positron emission tomography (PET) and radiolabeled deprenyl estimated the half-life of MAO-B in human brain at 40 days (44). For clinical purposes, recovery of enzymatic activity and restoration of amine metabolism generally requires up to two weeks, presumably because the enzyme must be replaced by synthesis.
An immediate consequence of MAO inhibition is an elevation in the intracellular concentration of catecholamines, including 5-HT and other biogenic amines (tyramine, tryptophan, octopamine and PEA). Within a period of hours following amine accumulation, a decrease of neuronal firing can be demonstrated in serotonergic and noradrenergic neurons. The antidepressant response, however, may be delayed by 2–3 weeks and may depend not on the increase in neuronal amine content per se but rather on certain secondary and tertiary adaptive changes. Increases in intracellular amine levels result, via feedback inhibition, in a reduction in amine synthesis. Amines accumulating in the cytoplasm begin to enter amine storage vesicles. From there, they may either displace endogenous amines or be released as co-transmitters or partial transmitters. Clinical improvement in affective symptoms correlates best with a down regulation of b-adrenergic, a2-adrenergic, and 5-HT2 receptors seen after two weeks. This effect is observed with nonselective MAOIs and selective MAO-A inhibitors, but only with high (nonselective) dosages of the MAO-B inhibitor deprenyl (28,76). Indeed, low-dose deprenyl produces only a marginal antidepressant response (88). This suggests a more central role for MAO-A (rather than MAO-B) in the treatment of depression.
Many of the effects of the MAOIs may be unrelated to MAO inhibition, though these have been less well studied. The MAOIs also inhibit other enzymes, including dopamine b-hydroxylase, 5-HT decarboxylase, choline dehydrogenase, succinic dehydrogenase and diamine oxidase. MAOIs may also directly inhibit the transport of amines; tranylcypromine appears to block both 5-HT and catecholamine uptake. The extent to which these actions contribute to the antidepressant effect of MAOIs is unclear. Even less clear is the role that changes in the levels of trace amines (e.g., PEA) play in the pathophysiology of mental illness.
Some of the actions and side effects of deprenyl and tranylcypromine may be due in part to their direct, amphetamine-like sympathetic stimulation (70). Clinical lore has it that these nonhydrazine agents have a faster onset of action than the substituted hydrazines and may help 'energize' patients. It has been suggested that the cyclized amphetamine structure of tranylcypromine can be opened to produce amphetamine. Although amphetamine has been detected in the blood after MAOI overdose (159), it is not usually found at therapeutic doses.
Kind regards,
Ed.
poster:ed_uk
thread:500450
URL: http://www.dr-bob.org/babble/20050516/msgs/500543.html