Monoamine oxidase inhibitors liver

CYP. cytochrome P450 isoenzyme HIV, human immunodeficiency vims INR, International Normalized Ratio LFTs, liver function tests MAOI, monoamine oxidase inhibitor PT, prothrombin time TCA, tricyclic antidepressant. 

Monoamine Oxidase inhibitors (MAOis). The first antidepressant discovered was iproniazid. This medication was developed in the early 1950s as a treatment for tuberculosis but was unexpectedly found to improve mood in depressed patients. It was later found that its antidepressant effect was due to its action on the MAO enzymes. Unfortunately, iproniazid was subsequently found to cause liver damage and was withdrawn from the market. 

Hydrazine is metabolized by rat liver microsomal enzymes to unknown products, ultimately yielding molecular nitrogen (Timbrell et al., 1982 Jeimer Timbrell, 1995). This was dependent upon oxygen and NADPH and was increased by NADH in the presence of NADPH. Hydrazine metabolism was 20-70% lower in human microsomes prepared from three individuals compared with rats. Hydrazine is also metabolized by rat liver mitochondria, but the monoamine oxidase inhibitors clorgyline and pargyline do not significantly decrease this activity (Jenner Timbrell, 1995). 

Monoamine oxidase inhibitors MAO is found in neural and other tissues, such as the gut and liver. In the neuron, this enzyme functions as a "safety valve" to oxidatively deaminate and inacti vate any excess neurotransmitter molecules (norepinephrine, dopamine, or serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors2 may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumu late 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. 

The monoamine oxidase inhibitors epitomize cyclical fashions in drug use and the impact of adverse effects. They were the first psychotropic drugs for which a clear biochemical action was defined. Early excitement was quickly tempered by reports of liver toxicity with the hydrazine derivatives, leading to synthesis of the cyclopropylamine drug, tranylcypromine, which in turn elicited the food and drug interactions that led to an overall decline in popularity. 

Monoamine oxidase inhibitors are rapidly and completely absorbed orally reaching peak blood levels within 2 h. Monoamine oxidase inhibitors are acety-lated in the liver to many active and inactive metabolites. The volume of distribution is estimated to range from 1 to 41 kg The inactive metabolites are excreted by the kidneys. The elimination half-lives of monoamine oxidase inhibitor parent compounds range from 15 min to 3.5 h. The biologic half-life often significantly exceeds the elimination half-life. 

MONOAMINE-OXIDASE-INHIBITORS(MAOIs) acton monoamine-oxidase (MAO) enzymes that are involved in the degradation of monoamines in the peripheral and central nervous system. Monoamine oxidase occurs within cells bound to the surface of the mitochondria. It is found not only within monoaminergic neurons, but also in the liver and intestinal epithelium. The enzyme converts amines to their corresponding aldehydes, which in the periphery are converted to their carboxylic acids by aldel e dehydrogenase. Neurotransmitters degraded by monoamine oxidase include dopamine. 5-hydnngrtryptamine and noradrenaline. 

Diphenoxylate is an opiate (schedule V) with antidiarrheal properties. It is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. Diphenoxylate shonld be used cautiously in patients with obstructive jaundice because of its potential for hepatic coma, and in patients with diarrhea cansed by pseudomembranous colitis because of its potential for toxic megacolon. In addition, it should be used cautiously in the treatment of diarrhea caused by poisoning or by infection by Shigella, Salmonella, and some strains of E. coli because expulsion of intestinal contents may be a protective mechanism. Diphenoxylate should be used with extreme caution in patients with impaired hepatic function, cirrhosis, advanced hepatorenal disease, or abnormal liver function test results, because the drug may precipitate hepatic coma. Because diphenoxylate is structurally related to meperidine, it may cause hypertension when combined with monoamine oxidase inhibitors. As a narcotic, it will augment the CNS depressant effects of alcohol, hypnotic-sedatives, and numerous other drugs, such as neuroleptics or antidepressants that cause sedation. 

Some of the monoamine oxidase inhibitors prolong the hexobarbitone sleeping time in mice, probably because they inhibit barbiturate breakdown by the liver microsomes . An anticonvulsive action has also been reported . The fact that the hydrazine derivatives interact with pyridoxal phosphate and can thus inhibit GABA formation may explain why some of the inhibitors of this type sometimes have a convulsive action also. 

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. 

Monoamine Oxidases and their Inhibitors. Table 1 Substrate specificity of the two forms of rat liver and brain monoamine oxidase... 

Fowler CJ, Mantle TJ, Tipton KF. The nature of the inhibition of rat liver monoamine oxidase types A and B by the acetylenic inhibitors clorgyline, 1-deprenyl and pargyline. Biochem Pharmacol 1982 31(22) 3555-3561. 

The harmala alkaloids harmaline (368 X = NH) and harmi.ne (369 X = NH) are active reversible inhibitors of monoamine oxidase (MAO). Benzo[ Jthiophene analogs of harmaline (368 X = S) and harmine (369 X = S), when tested in vitro as inhibitors of rat liver MAO, showed that (368 X = S) was 50 times more potent than harmaline, but (369 X = NH or S) were equivalent in potency. The replacement of the indolic nitrogen by sulfur greatly increased the lipid solubility of the molecule, which was reflected in the physiological disposition of the two analogs. 

Monoamine oxidase (MAO) inhibitors Foods containing tyramine (liver, pickled herring, cheese, bananas, avocados, soup, beer, wine, yogurt, sour cream, yeast, nuts) Palpitations, headache, hypertensive crises... 

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