Enzyme Kinetics - Irreversible Inhibitors

Irreversible Inhibitors - Practical Examples

These amines are found in abnormally low concentrations in the brains of depressed individuals. The question is "How can the concentrations of the amines be increased?" There are actually several ways, but it turns out that the easiest and most practical way is to prevent their break down. In other words, give the patients a MAO inhibitor. And this is what is done. There are several such inhibitors available. One is phenelzine or Nardil.

What we really want to know, to properly follow this disease, is the level of MAO in the brain. But we cannot find that out so the the level in the red blood cells is measured. It turns out that when the MAO is inhibited 80-90%, the depression disappears. This illustrates the therapeutic use of enzyme inhibitors.

What is more, a physician can determine whether the patient is complying, i.e. taking the proper dose, by measuring the red blood cell MAO. If the MAO is normal the patient is not taking his/her pills. On the other hand, if it is a new drug and the patient has 10% of the normal activity but is still depressed, it is obvious that for some reason the drug is not preventing amine oxidation in the brain. A different drug or a new approach is called for.

The same system can be used to illustrate the importance of specificity in medicine since this therapy is not without side effects. Certain foods contain another biogenic amine, tryptamine. These foods include mature or aged chesses (blue, Swiss etc.), dried salted fish, and some red wines. In a normal individual tryptamine is rapidly destroyed by MAO because its specificity is broad and, in fact, it has a very high affinity for the enzyme. However, if the MAO is inhibited, the tryptamine is not destroyed and can cause extreme hypertension. There have been reports of deaths caused by ingesting foods high in tryptamine while on MAO inhibitors.

The common MAO inhibitors are irreversible in nature. This means that once the patient is taken off the drug the MAO level does not return to normal very rapidly. One has to wait for the synthesis of new enzyme, and this takes about two weeks.

It has long been known that there are two kinds of MAO, type A and type B. Type A acts only on tryptamine but type B oxidizes the norepinephrine, seratonin and tryptamine. All of the inhibitors currently available inhibit both types. But there is a new drug which is due out soon which will act only on type B MAO. The advantage is that a patient on this drug can eat tryptamine containing foods without having the danger of hypertension.

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