Mechanism Of Action Of Tricyclic Antidepressants

Destroy Depression

How I Healed my Depression

Get Instant Access

The termination of action of biogenic amines norepinephrine (NE) and serotonin (5-HT) is determined by reuptake into the presynaptic terminal. Drugs that block reuptake, such as tricyclic antidepressants, increase the efficacy of those transmitters by allowing them to remain in the synaptic cleft and activate the receptors longer (Figure I-51).

It should be noted that although the exact mechanism of action of TCAs as analgesics is not known, there appears to be a close relationship between the inhibitory reuptake effects on biogenic amines and analgesic potency. While selective inhibitors of serotonin reuptake are less effective in treating pain, the ability to inhibit norepineprine reuptake is associated more strongly with analgesia. The dose of TCAs is lower than those dosages used to treat depression, suggesting that the analgesic properties are independent of their antidepressant properties.

Aside from TCAs specific antidepressant activity, neuronal hyperexcitability associated with pain is reduced through the mechanism of a decrease in sodium channel activity and GABAa-receptor channel activation. The net effect of these actions by anticonvulsants is to reduce the excitatory synaptic transmission or to enhance the inhibitory synaptic transmission. For instance GABA, which is an inhibitory ligand binds to the GABAA-receptor, thus opening the GABAA-channel, which hyperpolarizes the cell and inhibits further impulse generation. The GABAA-channel has at least five different binding sites (Figure I-52).

In addition, there are three different kinds of sites at which anticonvulsants exert their action:

1. Voltage-gated ion channel of the sodium/calcium type

2. Ligand-gated ion channel receptors

3. Combination of voltage-gated and ligand-gated ion channel/receptors

The ligand-gated ion channel binds excitatory neurotransmitters such as glycine and glutamate on the extracellular portion of the receptor. Via secondary intracellular phosphorylation process of protein kinases, a nearby ion channel opens for Na+-and K+-ions, causing an end-plate potential with either depolarization or hyperpo-larization of the postsynaptic neuron, depending on whether the ligand which binds to them is of excitatory or inhibitory nature (Figure I-53).

There are four main types of voltage-dependent calcium channels, each composed of several subunits: L-Type, T-Type, N-Type and P-Type. Each type of calcium channel is activated and inactivated at different voltage ranges and at different rates. Representative examples are ethosuximide and valproic acid which inhibit ion flow through the calcium T-channel (Figure I-54). The newer voltage dependent calcium

Ssri Action

Figure I-50. Summary of schematic representation of the targets receptor sites and their mode of action of different analgesics

Tricyclic Antidepressants
Figure 1-51. Tricyclic antidepressants (TCAs) acting at the descending noradrenergic- and serotonergic inhibitory pain pathways, thus relieving pain

channel blocker pregablin acts via the alpha2-subunit resulting in a modulation of the hyperexcited neuron (Figure I-54).

Another type of a voltage-gated channel is selective for the sodium ion. The sodium channels open in response to membrane depolarization, allowing an inward shift of sodium ions into the neuron, thus increasing neuronal depolarization and the spread of action potentials. After the channel closes, it remains inactive for a certain

Activity in tigand-gated ion channel

Was this article helpful?

0 0
Beat Depression Today

Beat Depression Today

I know this is hard for you to believe. I mean, to be able to be totally free of depression in such little time... and without any effort... not to mention the freedom to live your life, appear hard to fulfill at first glance... That is until you know the facts On a subconscious level, you will experience an incredible and exclusive Tri- Enhanced trance state of hypnosis to reprogram your mind to free you from negatize emotions.

Get My Free Ebook

Post a comment