Route of administration<unk> s are delivered orally, usually in the form of capsules or tablets. It is recommended to take<unk> s in the morning with breakfast, which does not affect drug levels, but may help with certain side effects. Norepinephrine has activating effects in the body and therefore can cause insomnia in some patients if taken at bedtime.<unk> s can also cause nausea, which is usually mild and goes away within a few weeks of treatment, but taking the medication with food can help alleviate this. The drugs themselves are usually a fine crystalline powder that diffuses into the body during digestion. Dosage Dosages vary depending on the<unk>  used due to varying potencies of the drug in question as well as multiple strengths for each drug. Mode of action The condition for which<unk> s are mostly indicated, major depressive disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signaling. Based on the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depressive symptoms, the following relations were determined: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; lack of serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life."<unk> s work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in increased extracellular concentrations of serotonin and norepinephrine and, consequently, an increase in neurotransmission. Most<unk> s including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin. Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs. Recent studies have shown that depression may be linked to increased inflammatory response, thus attempts at finding an additional mechanism for<unk> s have been made. Studies have shown that<unk> s as well as SSRIs have significant anti-inflammatory action on microglia in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs that acts in combination with the previously understood mechanism exist. The implication behind these findings suggests use of<unk> s as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. However, regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice. Pharmacodynamics Most<unk> s function alongside primary metabolites and secondary metabolites in order to<unk> euptake of serotonin, norepinepherine, and marginal amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain. The evidence also suggests that dopamine and norepinepherine behave in a co-transportational manner, due to the inactivation of dopamine by norepinephrine reuptake in the frontal cortex, an area of the brain largely lacking in dopamine transporters. This effect of<unk> s results in increased dopamine neurotransmission, in addition to the increases in serotonin and norepinephrine activity. Furthermore, because<unk> s are extremely selective, they have no measurable effects on other, unintended receptors, in contrast to monoamine oxidase inhibition. Pharmaceutical tests have determined that use of both<unk> s or SSRIs can generate significant anti-inflammatory action on microglia, as well. Activity profiles +<unk> s at the human and Compound ~Ratio( : ) Ki Ki Venlafaxine 7.8 145 1,920 1420 30:1 Des-venlafaxine 40.2 47.3 558.4 531.3 14:1 Duloxetine 0.07 3.7 1.17 20 10:1 Atomoxetine 87 5.4 0.06:1 (1:16) Milnacipran 8.44 151 22 68 1.6:1 Levo-milnacipran 11.2 19.0 92.2 10.5 1:2 All of the Ki and IC50 values are . The / ratio isbased on IC50 values for the and . Pharmacokinetics The half-life of venlafaxine is about 5 hours, and with once-daily dosing, steady-state concentration is achieved after about 3 days, though its active metabolite desvenlafaxine lasts longer. The half-life of desvenlafaxine is about 11 hours, and steady-state concentrations are achieved after 4 to 5 days. The half-life of duloxetine is about 12 hours (range: 8–17 hours), and steady-state is achieved after about 3 days. Milnacipran has a half-life of about 6 to 8 hours, and steady-state levels are reached within 36 to 48 hours.
Serotonin–norepinephrine reuptake inhibitor
Serotonin–dopamine reuptake inhibitor
Norepinephrine reuptake inhibitor
Glycine reuptake inhibitor
Dopamine reuptake inhibitor
Monoamine reuptake inhibitor
Serotonin–norepinephrine–dopamine reuptake inhibitor
Excitatory amino acid reuptake inhibitor