Monoamine oxidase inhibitors

Monoamine oxidase inhibitors

The last class of drugs we will consider are the inhibitors of monoamine oxidase (MAO). When we compare the re-action products in Figure 10.3 and in Figure 10.20b, re-spectively, they look fairly different¹⁴; yet both may be accounted for by the enzymatic mechanism outlined in Figure 10.21a in simplified form ¹⁵. The enzyme reaction starts with the abstraction of an electron from the substrate, which converts both the substrate and the enzyme to rad-icals. Subsequently, the substrate is dehydrogenated to a Schiff Base, which in turn is hydrolyzed to an aldehyde. Hydrogen and electrons wind up bound to the FAD pros-thetic group of the enzyme.

The hypothetic reaction mechanism for the inhibitor tranyl-cypromine is shown in Figure 10.21b. Abstraction of the first electron causes the (instable) cyclopropyl ring to open, and the radical thus formed recombines with the one formed at the enzyme to yield a covalent adduct. Because of this covalent attachment to the enzyme, the effect of MAO inhibitors outlasts the elimination of the drug and is only reversed by synthesis of new enzyme, which will re-quire days to weeks after discontinuation.

MAO inhibitors will act peripherally and may act centrally, again depending on their pharmacokinetic properties. They have, like reserpine, been used for both antihypertensive and antipsychotic treatment but now been superseded by more selectively acting drugs. However, there recently has been renewed interest in the development of MAO B-selec-tive inhibitors, since that enzyme subtype acts preferential-ly on serotonin and in the central nervous system; some of the side effects could thus be avoided or ameliorated. MAO B inhibitors have also been reported to increase the lifetime of dopamine and therefore to be beneficial in Parkinson's disease; similarly, inhibitors of COMT have more recently been introduced as a supplement to therapy in this disease.

Hello, wake up. So, why should MAO inhibitors have an antihypertensive effect? Decreased degradation of catecholamines should increase the availability of nore-pinephrine and increase rather than decrease blood pres-sure, shouldn't it? My textbook says that it works as fol-lows (Figure 10.22): Small amounts of tyrosine will always get decarboxylated to tyramine. Normally, tyramine is scavenged by monoamine oxidase. However, if this path-way is blocked, tyramine will get converted instead to oc then act as a false transmitter, in the same way as discussed above for guanethidine and methyl-DOPA.

Nice huh? But most likely wrong. The same text does not fail to mention the so-called ‘cheese reaction’, which consists in a sudden rise of blood pressure in patients receiving MAO inhibitors. Cheese – as well as other types of fermented food, such as salami or summer sausage – is rich in decarboxylation products of amino acids (amines), which are in part responsible for the characteristic flavours. The one of interest here is indeed tyramine16. Tyramine acts as an ‘indirect sympathomimetic’, much in the same way as amphetamine does. It can hardly be held responsible for lowering and increasing the blood pressure at the same time.