PubMed · 9989160
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D Pringuey, F Kohl, S Thauby, P Robert. 1999-01-15. [Antidepressive agents].. https://pubmed.ncbi.nlm.nih.gov/9989160/
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Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.
Antidepressants, particularly tricyclic antidepressants, have been a mainstay in the prophylactic therapy of migraine. The tricyclic antidepressants amitriptyline, nortriptyline, and doxepin have been the major agents for prophylactic treatment of migraine. These cause significant side effects in some patients. The high-affinity selective serotonin reuptake inhibitors and other newer antidepressants have been disappointing and much less effective in the treatment of migraine. In patients who are depressed with severe migraine, a tricyclic antidepressant may treat both conditions; however, the addition of a newer atypical antidepressant may be needed.
Distribution of a drug in the body is dependent on its permeation properties, the blood flow rates in various tissues, and on plasma and tissue uptake. The distribution of drugs in vivo is largely determined by uptake competitions between blood and tissues, as well as competitions among individual tissues. Basic lipophilic drugs are characterized by extensive accumulation in tissues, which leads to a high volume of distribution. Nonspecific binding to cellular membranes and uptake by acidic compartments (mainly lysosomes) are responsible for such a distribution pattern. Lysosomal trapping is an important mechanism of distribution of basic psychotropic drugs; however, the tissue distribution of the aliphatic-type phenothiazine neuroleptic promazine, tricyclic antidepressants (TADs) and selective serotonin reuptake inhibitors (SSRIs) depends more on phospholipid binding than on lysosomal trapping, whereas in the case thioridazine and perazine, lysosomal trapping is as important for the tissue uptake as is phospholipid binding. Neuroleptics and antidepressants mutually inhibit their lysosomal uptake. A decrease in the intralysosomal drug concentrations in vivo leads to a shift of the drug from organs abundant in lysosomes (lungs, liver and kidneys) to those poor in these organella, e.g., the heart, which may be of clinical importance (cardiotoxicity). The brain is not a homogenous organ, i.e., the phospholipid pattern and density of lysosomes vary in its different regions. Therefore, the contribution of the two mechanisms (lysosomal trapping and tissue binding) to total drug uptake is different in areas of the brain. Both lysosomal trapping and binding to cellular elements for psychotropics are higher in the grey matter and neurons than in the white matter and astrocytes, respectively. Lysosomal trapping and distribution interactions of psychotropics take place mainly in neurons. A decrease (via a distributive interaction) in the concentration of psychotropics in lysosomes (depot) may lead to an increase in their level in membranes and tissue fluids (i.e., in concentrations and compartments relevant to their pharmacological action) and, in consequence, to enhancement of the drug binding to neurotransmitter receptors and/or transporters.