64 Review Article Monoamine oxidase Douglas G. Wells FrA~ACS, Andrew R. Bjorksten nsc inhibitors revisited The monoamine oxidase inhibitors (MAOI'S) were de- History veloped during the late 1950's as the first effective Isoniazid and its close relative iproniazid were introduced antidepressant agents. With the development of the for the treatment of tuberculosis in 1951.3 Zeller et al. 4 tricyclic antidepressants, their use was superseded by demonstrated enzyme inhibition of MAO by iproniazid, drugs which appeared to be generally more effective and and in 1957 it was first used for the treatment of lacked the dangerous side effect of hypertensive crises. depression: Iproniazid was withdrawn from the United Recently there has been a resurgence of interest in their States' market in 1960 because of instances of severe and use, prominently for atypical depressions but also for sometimes fatal hepatotoxicity, s Those agents in current anxiety states, obsessive-compulsive disorders, eating use (tranylcypromine, phenelzine, isocarboxazid and disorders, chronic pain syndromes and migraine. 1.2 pargyline, which in the U.S. is approved in the treatment Because of widespread belief among anaesthetists of hypertension only) are the result of efforts to synthesise concerning the likelihood of life-threatening cardiovascu- MAOI's having the benefits of ipronazid without its lar instability and central nervous system (CNS) dysfunc- adverse effects. An often quoted figure is that tranylcy- tion during anaesthesia and surgery when these agents are promine and phenelzine account for over 90 per cent of all present, usual recommendations have been to withdraw the MAOI's currently prescribed. ''7 Because these data them two to three weeks before surgery. A growing were collected in the 1960's, 8'9 they may not accurately awareness of the relative safety of these agents has led to reflect contemporary usage. A host of second generation questioning of this policy. The true incidence of those relatively type-selective MAOI's may soon be introduced. previously reported adverse drug effects was and is unknown, but certainly they occur in a very small minority of patients. The MAO enzyme system Although firm epidemiologic data of recent years are MAC) is a flavin-containing enzyme found principally on lacking, anaesthetists may encounter increasing numbers outer mitochondrial membranes. The active form is a dimer consisting of two subunits, each having a molecular of patients receiving MAOI's. The purpose of this review is to present the modem understanding of the MAO weight of approximately 60,000 daltons. It functions via system, its drug inhibitors and relevant drug interactions oxidative deamination to inactivate over 15 monoamines in order that rational clinical decisions can be taken formed in the body, some of which serve important roles concerning these agents and the anaesthetic problems as synaptic neumtransmitters or neuromodulators, e.g., which can arise in their presence. dopamine, 5 hydroxytryptamine (5 HT), norepinephrine and epinephrine. ~o MAO is present in most tissues of all vertebrate species.~t Monoamine oxidase has been divid- ed into two subtypes (MAO-A and MAO-B) on the basis Key words of the different substrate specificities of the two forms. ~2 INTERACTIONS(DRUG): monoamine oxidase inhibitors, There is now growing immunochemical evidence that the sympathomimetic amines, meperidine, barbiturates; two forms are distinct isoenzymes of different molecular PHARMACOLOGY: monamine oxidase inhibitors. weight (63,000-67,000 for MAO-A vs 60,000-63,000 for MAO-B) as they yield different peptide fragments in mapping studies and have different electrophoretic behav- From the Departmentof Anaesthesia, Amalgamated Melbourne iour. ,3:4 Even more recently, a monoclonal antibody has and Essendon Hospitals, Melbourne, Victoria, Australia. been raised to human platelet MAO-B which cross-reacts Address correspondence to: Dr. Douglas G. Wells, with human liver MAO-B but not with liver or placental Department of Anaesthesia, C/O Post Office, The Royal MAO-A. is Melbourne Hospital, Victoria. 3050, Australia. Substrates for MAO can be divided into three broad CAN J ANAESTH 1989 / 36: I / pp64-74 Wells and Bjorksten: MONOAMINE OXIDASE INHIBITORS 65 TABLE Substratesand inhibitorsof MAO MAO-A Mixed MAO-B Subsuates epinephrine m,p-tyramine ~-phenylethylamine norepinephrine dopamine phenylethanolamine metanephrine octopamine o-tyramine serotinin(5-HT) synephrine benzylamine tryptamine N-methyltryptamine N,N-melhyltryptamine Irreversibleinhihitors clorgyline phenelzine (-)deprenyl Lilly 51641 tranylcypromine Lilly 54781 isocarboxazid MDL 72145 pargyline(more B) AGN 1133 AFN 1135 Reversibleinhlbitars harma|ine amiflamine cimoxatone moclobemide brofaramine(CGP 11305A) Ro 11-1163 MD 780515 FLA. 336(+) categories on the basis of the affinity of the two ing on the tissues considered. The target function of the isoenzymes for them, namely MAO-A specific, MAO-B use of MAO inhibitors in depression is the regulation of specific and mixed substrates for which the two enzyme monoamine content within the nervous system. Here forms have approximately equal affinity (Table). How- MAO metabolises neurotmnsmitters and transmitter syn- ever, it must be remembered that the substrate specificity thesis byproducts both intraneurally and in combination is only relative as it is highly concentration depen- with catechol-o-methyl transferase (COMT) extraneural- dent.16' 17 As the substrate concentration is increased the ly. Due to its location in the outer mitocbondrial mem- specificity becomes less apparent and it is now obvious brane, 2t MAO in neurons is only capable of deaminating that both forms of MAO are capable of metabolising all substrates that are free within the cytoplasm, being unable substrates if presented at an appropriate concentration, t6 to gain access to substrates once they are bound within MAO inhibitors may also be divided into three catego- storage vesicles. As a result the cytoplasmic concentra- ries on the basis of their specificity for the two enzyme tion of monoamines is maintained at a very low level. subtypes (Table), but like the substrate specificity, the MAO-A may have a higher affinity for synthesis by- specificity of the selective inhibitors is also dose-dependent products, such as tryptamine and octopamine, than for the and disappears at higher doses.IS transmitters noradrenaline and dopamine, maintaining the The picture is further complicated by differences in purity of neurotransmitters by preventing the build-up of localisation of the MAO isoenzymes. In humans (there these compounds in the storage vesicles, t] In addition are considerable species differences) platelets contain intraneuronal MAO-A probably forms the last line of exclusively MAO-B, placenta exclusively MAO-A, j4 defence against circulating indirectly acting sympathomi- liver has slightly more MAO-A activity than MAO-B metic amines which, without MAO, would be free to while intestine slightly less. ~9 About 60 per cent of human enter the cytoplasm of nerve terminals and ultimately brain MAO activity is of the A subtype, t9 Monoaminergic displace the normal transmitters from their storage vesicles. neurons appear to contain mostly MAO-A, with the Other tissues with high MAO content include liver, exception of serotonergic neurons which appear to con- kidney and lung ~9 where the enzyme performs a defensive tain a considerable amount of MAO-B. 2~ Extraneuronal function inactivating circulating monoamines. 22 In par- cells contain mostly MAO-B.2~ Although it appears likely ticular, they appear to form the first line of defence against that such a large degree of compartmentalism is likely to monoamines absorbed from foods, such as tyramine and produce functional consequences they are far from clear at [3-phenyl ethanolaraine, which would otherwise produce present. 2~ an indirect sympathomimetic response resulting in the Monoamine oxidase has two major functions depend- precipitous rise in blood pressure known as the "cheese 66 CANADIAN JOURNAL OF ANAESTHESIA effect." MAn is also associated with the blood-brain and Tyrosine gut-blood barrier where it probably performs a similar /~/o: ~17:2~7,.;. (~ function. 22 pa L-. -(b) MAn inhibitors Inhibition of neuronal MAn (i.e., MAn-A) produces a ,, -- ..... (o) demonstrable increase in both the monoamine content of brain and the cytoplasmic concentration of MAn sub- strates within a few hours.2a While the therapeutic action was originally believed to be due to this amine accumula- tion, 2'* recent evidence has cast considerable doubt on this view. There are several secondary adaptive responses to the .(f) increased amine levels. A reduction of amine synthesis by end-product inhibition of tyrosine hydroxylase has been clearly demonstrated within the noradrenergic system25 and also for serotonergic neurons26 after treatment with FIGURE Neuronal consequences of chronic MAn inhibition in an MAn inhibitors. adrenergic neuron. NE = norepinephrine, E = epinephrine, DA = The increased cytoplasmic levels of synthesis byprod- dopamine, T = tyramine, O = octopamine. (a) end-product inhibition UCtS, which may increase up to 30 times their normal of transmittersynthesis enzymes; (b) accumulationof false concentration in contrast to norepinephrine and dopamine transmitters in storage vesicles; (c) increased cytoplasmic amine which only increase about two-fold,2a begin to enter concentration; (d) slimulation of inhibitory pre-synaptie receptors