Mechanism Of Action Of Tricyclic Antidepressants Pdf Download BETTER
Antidepressants are among the oldest drugs used for the treatment of neuropathic pain and have been the subject of many randomized controlled trials. They originally came to be used in the treatment of chronic pain, and in particular neuropathic pain, because some of the patients suffering from chronic pain are also depressed, and these drugs relieve pain as well as depression. However, an independent analgesic action has been reported for TCAs since the 1960s. Pain relief has since been described in depressed and non-depressed patients with chronic pain. The relief can be more rapid in some patients and appears to occur at a lower dose than the antidepressant effect . An early concept of the mechanism of antidepressant analgesia was that these drugs are capable of potentiating the activity of the descending inhibitory pathways extending from the brain stem to the dorsal horn of the spinal cord, mainly by inhibiting the reuptake of serotonin and noradrenaline that descending fibers release into the spinal synapses between nociceptors (or first-order neurons) and the spinothalamic neurons (or second-order neurons). At this level, neurotransmitters can inhibit synaptic transmission between first- and second-order neurons directly, by binding to membrane receptors expressed on the surface of these neurons, as in the case of noradrenaline that binds alpha-2 adrenergic receptors. Alternatively, they can activate interneurons that in turn release inhibitory substances such as endogenous opioids or gamma-aminobutyric acid (GABA), as in the case of serotonin at its metabotropic receptors or noradrenaline at alpha-1 adrenergic receptors . Recently, some studies highlighted a possible peripheral mechanism for the action of antidepressants. Bohren and colleagues examined the effect of noradrenergic lesions at different levels of the nervous system and concluded that the analgesic properties of long-term nortriptyline rely on the peripheral noradrenergic system (whereby the sympathetic fibers sprouting in the dorsal root ganglia that accompany the nerve injury are the source of noradrenaline) .
Mechanism Of Action Of Tricyclic Antidepressants Pdf Download
Pregabalin and gabapentin are both derived from GABA, but they have no effect on the GABAergic system. Their mechanism of action includes binding to the alpha-2/delta-1 subunit of the voltage-gated calcium channels in several areas of the central nervous system (CNS) and spinal cord in which these channels are expressed, and this is sufficient to explain their analgesic, anxiolytic, and anticonvulsant pharmacological properties . Voltage-gated calcium channels are localized on presynaptic terminals, where they control neurotransmitter release. Being voltage-sensitive, they open in response to action potentials arising from the periphery and allow the influx of calcium ions, which is essential for the fusion of synaptic vesicles and release of neurotransmitters into the synaptic cleft (Fig. 1). This is the general mechanism by which these channels are involved in neurotransmitter release in the spinal cord and in various areas of the CNS. Voltage-gated calcium channels are comprised of different subunits: the alpha subunit is responsible for the formation of the pore through which calcium ions enter into the cell, whereas the alpha-2/delta-1, beta, and gamma are accessory subunits. The alpha-2/delta-1 subunit is responsible for the trafficking, localization, and stabilization of the channel in the plasma membrane. Interestingly, it has been demonstrated that the alpha-2/delta-1 subunit binds at one site to the alpha-1 subunit and at another site to thrombospondin, a protein of the extracellular matrix which is produced by activated astrocytes. Since in experimental models of neuropathic pain thrombospondin appears to be upregulated, it is possible to speculate that the activation of astrocytes in the spinal cord as a consequence of nerve injury and the abnormal secretion of thrombospondin promote the stabilization of voltage-gated calcium channels at the presynaptic terminal (Fig. 2). Indeed, it has been shown that the number of voltage-gated calcium channels increases in neuropathic pain conditions and may sustain an aberrant neurotransmission in the spinal cord. Therefore, it is likely that gabapentinoids, by binding to the alpha-2/delta-1 subunit, destabilize the macromolecular complex that keeps the calcium channel on the surface of the presynaptic terminal, promoting its internalization . Thus, gabapentinoids have no direct effect on the currents, but instead influence the number of available calcium channels in the plasma membrane.
Strong opioids, such as morphine, oxycodone, and hydromorphone, and weak opioids, such as tramadol, are efficacious when compared with other drugs used for neuropathic pain and are similar to antidepressants in terms of the numbers needed to treat . Nevertheless, they have always been considered second-line drugs , and more recently third-line drugs , due to adverse drug reactions and concerns about abuse, diversion, and addiction. Tapentadol represents a new class of dual opioid analgesics, combining a less potent agonistic activity at mu-opioid receptors with inhibition of noradrenaline uptake, and exploiting the synergy between the two mechanisms. The innovative pharmacodynamics and a favorable pharmacokinetic profile make tapentadol a unique opioid analgesic. However, the paucity of available studies prevented tapentadol from being included in the most recent systematic review and meta-analysis on neuropathic pain [20,21,22]. For this reason it will not be further discussed in this review.
The analgesic effect of opioids is due to their action in the brain, brainstem, spinal cord, and, under certain circumstances, on peripheral terminals of primary afferent neurons. All endogenous opioid peptides, including β-endorphin, enkephalins, and dynorphins, bind to seven transmembrane G protein-coupled receptors, which are divided into three classes: mu, delta, and kappa receptors. Opioid receptors are coupled to inhibitor G proteins, with receptor activation inhibiting the adenylate cyclase as well as the intracellular production of cAMP. However, the coupling of opioid receptors to calcium and potassium channels is thought to be a central mechanism of analgesia production by both endogenous and exogenous opioids.
Although new innovative molecules are needed for the successful cure of neuropathic pain, a deeper understanding of the mechanism of action of currently available drugs is an essential step towards an effective clinical approach that tailors therapies both to the specific neuropathic disease and to the needs of an individual patient.
Antidepressants are one of the most frequently prescribed drug classes in Western countries [1,2,3]. They have broad therapeutic indications, from depression to anxiety or obsessive-compulsive disorders, but also enuresis, chronic pain or eating disorders. The most important classes of antidepressants are serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Antidepressants act mainly through the monoamine neurotransmitters, serotonin and noradrenaline [4, 5]. They can induce several adverse drug reactions , including digestive disorders, sexual dysfunction, fatigue or sleepiness, but also hyponatremia, hepatitis , or bleeding.
Movement disorders are clinical syndromes with either an excess or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. They include extrapyramidal symptoms (akathisia, tardive dyskinesia, dystonia, and parkinsonism) but also a wide range of disorders, from tremor to tics and bruxism, to name a few. Although not the most frequent adverse drug reactions of antidepressants, antidepressant-induced movement disorders have been described and can lead to severe and disabling conditions [8,9,10]. Reports of extrapyramidal symptoms associated with antidepressants have been documented for SRIs, SNRIs, and other antidepressants . Nevertheless, there are few studies specifically designed to address this association. A recent observational study found a harmful association between the incidence of parkinsonism or associated extrapyramidal symptoms and use of antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine . Furthermore, the heterogeneity of movement disorders and the difficulty to correctly label them is a limitation to the quality of the few existing studies. Lastly, the frequent use of psychoactive comedications prone to also induce movement disorders, such as antipsychotics, mood stabilizers or antiepileptics, in patients receiving antidepressants, makes it difficult to precisely assess the level of imputability .
Second, using the extraction of 1,027,405 reports containing at least one antidepressant, we ranked increased movement disorders reporting according the four classes of antidepressants and the 58 antidepressants. We used adjusted logistic regression models and results were expressed as adjusted RORs (aRORs) on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders (see details in Tables 2 and 3 of the ESM). We excluded reports with missing values for these factors, reports without detailed adverse drug reactions, and reports containing more than one antidepressant. We also excluded outlying data on patient age.
One cluster of antidepressants-induced movement disorder are extrapyramidal symptoms which include akathisia, tardive dyskinesia, dystonia, and parkinsonism. Although the precise mechanism of the association between extrapyramidal symptoms and antidepressants is not precisely known, it has been proposed that the increase in the availability of serotonin could indirectly inhibit dopamine release in the striatum by increasing the stimulation of 5-HT2 receptors [11, 26]. Within this theoretical framework, the variation in affinity for 5-HT2 receptors between antidepressants may explain the differences in the frequency and the intensity of extrapyramidal symptoms seen in patients. A report using data from a multicenter drug-surveillance program on 15 patients between 1994 and 2016 , found that extrapyramidal symptoms frequently occurred with SRIs treatment alone (7/15 cases) or concomitant SRI treatment (6/15 cases) and were most frequent with escitalopram-treatment (5 cases). The authors found that the most common extrapyramidal symptom was atypical dyskinesia (6/15 cases) followed by akathisia (4/15 cases) and extrapyramidal symptoms occurred at any dosage and equally often in men and women. A recent nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015 and found a harmful association between extrapyramidal symptoms and duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine . In our study, citalopram, escitalopram, mirtazapine, and paroxetine were associated with akathisia, fluoxetine and paroxetine were associated with dystonia, and venlafaxine was associated with tardive dyskinesia.