Monoamine Oxidase Inhibitors Isocarboxazid Phenelzine Tranylcypromine Selegiline Moclobemide

Monoamine oxidase inhibitors (MAOIs) are less commonly prescribed than TCAs. Their use is one of last resort, when no other drugs can cure a patient's depression. As with TCAs, MAOIs are quite effective in "curing" patients experiencing severe depression and also atypical depression. Depression is termed atypical when an affected person sleeps more than normal and gains weight, the opposite effects of more commonly experienced depressive behavior such as insomnia and weight loss. Other depressive symptoms such as extreme fatigue during the day and feelings of hopeless and worthlessness are seen in both kinds of depression.

MAOI ACTION

Unlike TCAs, MAOIs do not interact with adrenaline or histamine receptors, so they present fewer sedative or jittery side effects than TCAs. However, MAOIs do have a serious risk factor associated with them. Specifically, when taken with certain foods they can cause a life-threatening hypertensive crisis.

When neurotransmitters are released into the synapse they are either taken up by transporters back into the neuron to be used again or are degraded. Recall that the monoamines serotonin, dopamine, and norepinephrine have similar chemical structures and, as such, they follow the same pathways of synthesis and breakdown. All monoamines are degraded by an enzyme called monoamine oxidase. MAOIs bind irreversibly (i.e., form covalent bonds) to the reactive site of monoamine oxidase.

Covalent bonding occurs when atoms share electrons with other atoms, creating a more stable molecule. It is very difficult to break such a bond because then the atoms become less stable. Due to the irreversible binding resulting from covalent bonding, the MAOI stays attached to the monoamine oxidase until the enzyme is broken down (enzymes usually get turned over every few weeks). Since serotonin and norepinephrine are no longer being broken down, their levels build up both inside and outside the neuron, which are continually being activated through receptors (Figure 2.2). This increase in action over time alleviates depression, although the precise mechanism is not fully understood.

MAOIs are sometimes termed as "hit and run" or "suicide" drugs since there is no way to unbind the MAOI from the active enzyme, thus their effects last even after the patient has stopped taking them. The body must produce new monoamine oxidases to replace the nonfunctioning MAOI-bound enzymes, a process that requires a few weeks. Thus it takes a long time for the effects of MAOIs to "wash out" of the body.

TYRAMINE (CHEESE) CRISIS

MAOIs prevent breakdown of not just serotonin, dopamine, and norepinephrine but also a similarly shaped molecule called tyramine. Tyramine is not a neurotransmitter and plays no role in the brain but does have a significant influence on blood pressure. Thus if tyramine levels rise too high, a hypertensive reaction can develop. With monoamine oxidase blocked, there is no way to clear ingested tyramine, potentially producing rises in blood pressure so extreme that a heart attack can ensue.

While patients are taking an MAOI, their diets must be closely monitored to make sure that foods that contain high tyramine levels are avoided. Tyramine is found in abundance in hard cheeses and wine (and quite a number of gourmet products). Meats that have been preserved, such as chicken liver, aged sausages, and pickled herring, are all high sources of tyramine.

\ NA aldehyde

DO PA (breakdown product)

Mechanism Action Moclobemide
Normal events at a noradrenergic synapse
Tricyclic Antidepressant Diagram

Drug effects at a noradrenergic synapse

Figure 2.2 Diagram of a noradrenergic (NA) synapse. After an NA neurotransmitter is recycled back into a neuron, the MAO enzyme breaks it down. MAOIs block the MAO enzyme, causing a buildup of NA neurotransmitters inside the neuron, so that more are released into the synapse. Tricyclics block the recycling of NA neurotransmitters back into the neuron.

Drug effects at a noradrenergic synapse

Figure 2.2 Diagram of a noradrenergic (NA) synapse. After an NA neurotransmitter is recycled back into a neuron, the MAO enzyme breaks it down. MAOIs block the MAO enzyme, causing a buildup of NA neurotransmitters inside the neuron, so that more are released into the synapse. Tricyclics block the recycling of NA neurotransmitters back into the neuron.

Even chocolate has high enough levels of tyramine to prevent people on MAOIs from eating more than small amounts of it. Other foods such as figs, soy sauce, or certain types of beans are also forbidden. For some people, being told to give up chocolate is too much to ask, while others can live on a tyramine diet with no sense of loss. But for those who do use MAOIs, vigilance and willingness to live with a slight sense of deprivation are two necessary requirements.

Even if a patient is able to follow a special diet, there are other predisposing factors that make MAOIs too risky to use. People with heart problems, high blood pressure, epilepsy, or asthma are all unsuitable candidates for MAOIs. There have also been incidences of liver damage (however, this kind of toxicity rarely occurs with MAOIs currently on the market).

NEW VS. OLD MAOIs

MAOIs can be classified into two groups: the irreversible (older) MAOIs such as Parnate® (tranylcypromine) and Nardil® (phenelzine), and the reversible (newer) drugs such as Manerix (moclobemide) and Deprenyl (selegiline). Older MAOIs have more side effects associated with them since their action is less specific than newer MAOIs.

Researchers have discovered that there are two types of monoamine oxidase enzyme: MAO-A and MAO-B, each located in different regions of the body. Older MAOIs, such as Nardil, inhibit both versions of monoamine oxidase, resulting in increased serotonin and norepinephrine inside the cell (and also leakage into the synapse, thus activating receptors). Increases in serotonin and noreinephrine receptor activation can lead to several over-stimulating side effects. These central nervous system effects include tremors, insomnia, agitation, and occasionally, precipitation of a mania in patients with bipolar depression.

Newer MAOIs are more specific in their action since they target only one of the two types of monoamine oxidase.

For instance, a recently introduced MAOI, selegiline, preferentially targets the B form of monoamine oxidase, which is found primarily within the brain. The other form of mono-amine oxidase, MAO-A, is located in the gastrointestinal tract and is associated with more of the older MAOI side effects. When selegiline is prescribed in the correct dose, there is negligible interaction with type A and thus fewer side effects. Also, since type A monoamine oxidase is the main enzyme that breaks down tyramine (because of its location in the stomach), patients taking selegiline are safely able to eat tyramine-rich foods. Monoamine oxidase binding in these newer MAOIs is reversible (unlike the older MAOIs, which form permanent attachments to the monoamine oxidase enzymes). Thus a new term has been created to differentiate them: reversible inhibitors of monoamine oxidase (RIMAs).

Selegiline marks a significant advance in the ongoing effort to decrease the side effects associated with MAOIs; but because it is taken in pill form, it is impossible to eradicate all of the binding to monoamine oxidases in the gastrointestinal tract. However, just recently Somerset Pharmaceuticals has developed a patch form of selegiline, which allows the drug to bypass the gastrointestinal tract. With this delivery system, less of the drug is broken down by the liver and more of it can reach the brain, its therapeutic target. However, the patch form also makes it more difficult to limit the amounts of selegiline entering the body, thus careful monitoring of the patient is required. (Selegiline also may have some dopamine uptake inhibition, which makes it potentially useful for Parkinson's patients.)

SEROTONIN SYNDROME

Another risk associated with MAOIs is the "serotonin syndrome," which arises when several drugs that modulate serotonin are taken at the same time. The syndrome is presumably caused by over-stimulation of the brainstem by a certain type of serotonin receptor (5-HT1A). Since the brainstem modulates cardiovascular and breathing functions, an overload of serotonin in the brainstem may potentially cause hypertension. Because of this, stimulants such as methylphenidate (Ritalin®), dopamine, epinephrine, and norepinephrine, or other antidepressants such as SSRIs or TCAs should be avoided due to the possibility of a hypertensive crisis. Also, the combination of MAOIs and tryptophan (found in some nutritional supplements and also turkey) has been reported to cause such side effects as disorientation, confusion, amnesia, hypomanic signs, and shivering.

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Responses

  • Karri
    Which would have the highest risk of serotonin syndrome selegline phenelzine moclobemide?
    7 months ago

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