Monoamine oxidase drugs acting

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

Monoamine Oxidase Inhibitors (MAOIs). MAOI autidepressauts were derived from drugs developed iu the early 1950s to treat tuberculosis. They act by iuterferiug with the MAO euzymes that metabolize aud thus elimiuate dopamiue, uorepiueph-riue, serotouiu, aud other related substauces. The MAO euzyme comes iu two varieties, MAO-A aud MAO-B. It is the MAO-B euzyme that metabolizes dopamiue. 

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

TABLE 15-2. Drugs acting on the noradrenergic system not involving an action at uptake sites or on monoamine oxidase ... 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

Monoamine oxidase inhibitors (MAOIs) are useful as thymoleptic (antidepressant) drugs, especially since the action of some of these agents is very rapid, as compared to the lag period of days or even weeks shown by tricyclic antidepressants. All MAOIs act by increasing the available concentration of the neurotransmitters NE and 5-HT which, because they are not metabolized, accumulate in the synaptic gap and exert an increased postsynaptic effect. The drugs show hypotensive activity as a side effect, and some MAOIs are used as hypotensive drugs. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

Substitutions at the a carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of -substituted compounds (Figure 9-5). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body they are indirectly acting sympathomimetics. 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a safety valve to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. 

Jacobsen suggested that the effects of the MAOI antidepressants such as iproniazid were clearly distinguishable from effects of stimulant drugs. Like Kline and colleagues, he assumed that their effects in depression were due to monoamine oxidase inhibition, but did not explain how they could be differentiated from stimulants which were also known to act in this way. 

A similar sentiment was expressed in a later British textbook of psychopharmacology Antidepressant drugs, like imipramine and the monoamine oxidase inhibitors differ from euphoriant drugs such as amphetamine in that they appear to act specifically against depressive symptoms (Dally 1967, p. 10). 

Fig. 1. A. Chemical structure of key molecules involved in the key steps in intracerebral synthesis and metabolism of dopamine. The successive steps are regulated by the enzymes tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and dopamine-p-hydroxylase (DBH). B. Structure of key toxins and other drugs acting on dopamine neurones, including 6-hydroxydopamine (6-OHDA), a-methyl tyrosine, and amphetamine. For further details see Iversen and Iversen (1981) or Cooper et al. (1996).

LINEZOLID - Drugs Acting on the Nervous System, Antidepressants, Monoamine oxidase inhibitors ... 

---