What was the first MAOI
- Iproniazid, an anti-TB agent
What are the MAOIs?
- Nonselective: hydrazine derivatives (e.g., isocarboxazid, phenylhydrazine) and nonhydrazine derivatives (e.g., tranylcypromine)
- Selective Reversible MAOAI: Moclobemide
- MAOBI: Selegiline
What are the subtypes and functions of MAO?
- MAO-A and MAO-B
- Both present in brain and other organs
- MAO-A mostly in D and NE neurons
- MAO-B mostly in 5-HT neurons
What are the main substrates for MAOA and MAOB
- The main substrates for MAO-A are epinephrine, NE, and 5-HT.
- The main substrates for MAO-B are phenylethylamine, phenylethanolamine, tyramine, and benzylamine.
- DA and tryptamine are metabolized by both isoenzymes.
What are the inherited disorders associated with MAOI?
- A rare inherited disorder, Norrie’s disease, is characterized by deletion of both genes; patients with this disorder have very severe mental retardation and blindness.
- Another rare inherited disorder is Brunner syndrome, caused by a mutation in the MAO-A gene. It is characterized by impulsive aggressiveness and mild mental retardation
What is the cofactor for MAO and where is the enzyme usually found?
- The enzyme is primarily found in the outer mitochondrial membrane;
- flavin adenine dinucleotide is a cofactor for both MAO-A and MAO-B.
Although DA is considered to be a mixed substrate for both MAO-A and MAO-B, the breakdown of DA in the striatal regions of the brain is preferentially by ....
What is the relationship of MAOA levels in the brain and major depression?
MDD is associated with higher MAOA in the brain
What is the mechanism of action of MAO?
- MAO is bound to the outer surface of the plasma membrane of the mitochondria
- MAO is unable to deaminate amines that are present inside stored vesicles and can metabolize only amines that are present in the cytoplasm.
- As a result, MAO maintains a low cytoplasmic concentration of amines within the cells. Inhibition of neuronal MAO produces an increase in the amine content in the cytoplasm.
- Initially, it was believed that the therapeutic action of MAOIs was a result of this amine accumulation, but secondary adaptive mechanisms might also have a role.
What is the effect of MAOIs after several week of treatment?
Reduction in the number of beta, alpha, 5HT2 and 5HT3 receptors
What are the MAOIs?
- hydrazine derivatives: phenelzine and isocarboxazid)
- nonhydrazine derivative: tranylcypromine
- irreversible MAOB inhibitor: Selegiline
- Reversible MAOA inhibitor: Moclobemide
What are other mechanisms of MAOIs?
- Inhibition of MAO uptake
- - tranylcypromine is similar to amphetamines and activating
What are the indications for MAOIs?
- Atypical depression
- Panic disorder (irreversible better; at first might worsen)
- Social anxiety disorder (irreversible better)
- Maybe GAD and PTSD (less evidence)
What is the significance of acetylation in patients on Phenelzine?
slow acetylators improve more with phenelzine than do fast acetylators
What is the comparable efficacy of MAOIs and SSRIs or TCAs in treating atypical depression?
MAOIs are superior to TCAs, but not SSRIs, in treating atypical depression
What are the most common Side effects of MAOIs?
- Dizziness, headache, dry mouth, insomnia, constipation, blurred vision, nausea, peripheral edema, forgetfulness, fainting spells, trauma, urinary hesitancy, weakness, and myoclonic jerks.
- Loss of weight and appetite may occur with isocarboxazid use
- Elevated liver enzymes
When is necessary to do LFTs in patients who are on MAOIs?
Liver function tests must be done when patients have symptoms such as malaise, jaundice, and excessive fatigue.