IO S.A. MEDICAL JOURNAL 2 January 1965 A REVIEW OF THE DANGERS OF MONOAMINE-OXIDASE INHIBITORS, WITH SPECIAL REFERENCE TO ANAESTHESIA JACK JACOBSON, M.B., CH.B., D.C.H., D.A., F.F.A.R.C.S., Department of Anaesthetics, Groote Schuur Hospital, Cape Town Although this article was designed primarily for the the appropriate emotional reactions. We have thus arrived guidance of anaesthetists, it should be of equally great at the stage where mood and behaviour are placed on a concern to surgeons, obstetricians, physicians, psychiatrists chemical basis. It is now known that 2 monoamines, and general practitioners. (physiologically important amines with only 1 amine The subject of anaesthesia has expanded tremendously radicle) appear to play a significant role. They are 5-HT in the last decade or two, and concurrently there have (serotonin) and noradrenaline, and they may act as trans­ been great developments in other fields as well, notably in mitters or modulators in the central nervous system, that of psychiatry. It is most important for anaesthetists to affecting mood and behaviour considerably. Other mono­ keep abreast of developments in other fields, as they often amines which may also well be involved are tyramine, have a very close bearing on their own. The perils which tryptamine, dopamine and adrenaline. they face daily, are continually increasing with the intro­ Storage duction of new drugs affecting anaesthesia, and possible iatrogenic catastrophes should figure prominently in their Both noradrenaline and 5-HT are found in high concen­ minds. trations in that part of the brain concerned with emotional The association between anaesthetists and psychiatrists behaviour; in the hypothalamus, reticular activating has always been a fruitful one, particularly since Bennett system and limbic system, very little monoamine being first used curare to soften the convulsions of electroconvul­ present in the cerebral cortex or cerebellum. They are sive therapy. However, this association is purchased at a stored in an inactive form, and it is suggested that at the price, often considerable and, unfortunately, sometimes correct movement, nerve impulses release their free forms supreme. During recent years anaesthetists have been which then stimulate the transmission of emotional re­ faced with a new menace in the form of a group of drugs action. used by psychiatrists, as well as by physicians and general Function practitioners. These drugs, known as the monoamine­ oxidase (MAO) inhibitorsl have been instrumental in Anaesthetists are familiar with the physiological great strides being made in the treatment of mental depres­ opposing actions of the sympathetic and parasympathetic divisions of the autonomic nervous system, but this takes sion,2, 3 but at the same time they offer nothing to the anaesthetist and merely add to his daily burden. To ignore no cognizance of the role these systems play in regulating them would be sheer folly, and in view of the fact that emotional behaviour. To understand psychiatric colleagues, very little mention has been made in respect of these and the drugs they use, one must grasp the concept of agents in anaesthetic literature, despite the fact that drug how the autonomic nervous system is integrated into the potentiation with MAO-inhibitors is theoretically more whole of the central nervous system. This in turn, involves liable to happen to anaesthetists as a group, because the an understanding of Hess and Brodie's division of the particular drugs potentiated are used more frequently by subcortical systems of the .central nervous system into 2 them than by most other groups in the profession, it was separate and antagonistic systems--ergotropic and tropho­ felt that a review such as this would serve a purpose. tropic. An outline will be given of the brain monoamines, It appears that, in fact, the sympathetic and parasympa­ notably 5-hydroxytryptamine (5-HT) and noradrenaline, thetic divisions of the autonomic nervous system are inte­ their origins, functions and fate and how they are inte­ grated into the central nervous system and play a vital part grated in the central nervous system to play their part in in regulating mood and behaviour, and each forms part of affecting mood and behaviour.· Consideration will be given the ergotropic and trophotropic systems. The theory is that to their relationship to mental depression and how they 5-HT and noradrenaline are involved in the functions of tie up with monoamine oxidase and MAO-inhibitors. After the trophotropic and ergotropic systems, acting as trans­ this, the actual drugs used will be mentioned, with mitters. Impulses arising from consciousness, viscera and reference to their uses and dangers, notably that of drug somatic supporting structures may pass to either of the 2 potentiation, the latter being that aspect of the paper coordinating systems and, by stimulating them, produce which is of greatest concern. Finally an attempt will be different effects through medium of either 5-HT or nor­ made to indicate how to avoid the pitfalls, and how to adrenaline. deal with emergencies. The ergotropic system consists of an integrated combi­ nation of sympathetic, reticular activating and somato­ BRAIN MONOAMINES sensory-motor systems. Stimulation thereof will result in Definition the release of the transmitter, noradrenaline, which then Also known as neurohormones, they are defined as activates the system to produce patterns of arousal with either transmitter substances, released from nerve endings psychic stimulation and heightened sympathetic activity, and activating the post-synaptic membrane, or substances features which are absent in mental depression. enhancing or inhibiting (modulating) the action of the The trophotropic system on the other hand, integrates transmitter.6 Their release stimulates the transmission of the parasympathetic system with the somato-motor-sensory 2 Januarie 1965 S.A. TYDSKRIF VIR GENEESKUNDE II system and the limbic systems, possessing 5-HT as trans­ oxidase. A few of the drugs mentioned have been withdrawn mitter. Stimulation of this system results in behaviour from the market as a result of toxic reactions. patterns of a relaxing and subduing nature with a general I. Hydrazines decrease in psychic, and increase in parasympathetic (a) Phenelzine ('nardil') activity; a state preparing the body for rest and sleep. (b) Iproniazid ('marsiIid') (c) Isocarboxazid ('marplan') It is felt that in mental depression there is an upset in (d) Nialamide ('niamid') balance between these 2 systems because of a disturbance (e) Etryptamine ('monase') in the hormones which regulate them, notably 5-HT and (f) Pheniprazine ('catron') noradrenaline. Which neurohormone is of the greatest (g) Phenoxypropazine ('drazine') (h) Mebanazine ('actomol') importance is, as yet, uncertain, but it would seem that a (i) Pivhydrazine ('tersavid') deficiency of 5-HT is of considerable significance in these 2. Nonhydrazines depressed states. A MAO-inhibitor will correct this upset (a) Tranylcypromine ('parnate') balance by increasing the brain concentrations of mainly (b) Tranylcypromine 5-HT, and to a lesser extent of noradrenaline.4,5 and Trifluoperazine (' parstelin') Synthesis and Destruction (c) Pargyline ('eutony[') The important monoamines are derived from the amino Phannacological Actionsl acids tyrosine and tryptophan. Many, but certainly not all of the effects of MAO-inhibitors oxidized are based on MAO-inhibition. I. Tryptophan -~ 5-hydroxytryptophan decarboxylated . MAO 1. Effects based on MAO-inhibition ---------+) 5-hydroxytryptamme ----+ 5-hydroxy-indoleacetic acid (5-HIAA) (a) Increase in tissue endogenous monoamines. Increased oxidized decarboxylated concentrations of monoamines occur in the brain, blood, liver, 2. Tyrosine -----+ L-dopa ) dopamine heart and gut after administration of a large dose of inhibitor. oxidized methylated The substances which are increased include 5-HT, noradrena­ ---+ noradrenalin ------+ adrenaline line, dopamine, tyramine and tryptamine, and this increase is related to the action of the MAO-inhibitor providing for a MAO I MAO decreased breakdown of monoamines. The increase in mono­ 1 ,} amines is probably responsible for the psychic stimulation and Vanilloyl mandelic acid VMA feeling of wellbeing, the chief action of a MAO-inhibitor VMA probably being that of excitation of the central nervous system. In this simplified version it will be noted that those (b) The effects of exogenous monoamines and their precur­ monoamines are broken down in the presence of a most sors is enhanced. important enzyme, monoamine oxidase. (c) Diminution of the effects of monoamine liberators (Reserpine). Normally reserpine releases brain monoamines Monoamine oxidase. Noradrenaline, 5-hydroxytrypta­ and depletes that organ of its stores. This action is antagonized mine, adrenaline, tyramine and tryptamine are all inacti­ by MAO-blockade, following pretreatment with a MAO­ vated by this enzyme monoamine oxidase, which exists in inhibitor, so that reserpine now no longer has sedative and hypothermic effects-in fact the opposite may occur. This is close association with these hormones, especially in the possibly due to the fact that the monoamines are liberated and subcortical levels of the brain and in the liver. This no monoamine oxidase is available for their degradation. inactivation can be prevented by the administration of a 2. Effects probably not Related to MAO-inhibition monoamine oxidase inhibitor, and, to recapitulate, it is (a)